Antiviral beta-amino acid ester phosphodiamide compounds

ABSTRACT

Compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     and their pharmaceutically acceptable salts are useful for the inhibition of HIV reverse transcriptase. The compounds may also be useful for the prophylaxis or treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antiviral agents, immunomodulators, antibiotics or vaccines.

BACKGROUND OF THE INVENTION

The retrovirus designated human immunodeficiency virus (HIV),particularly the strains known as HIV type-1 (HIV-1) and type-2 (HIV-2),have been etiologically linked to the immunosuppressive disease known asacquired immunodeficiency syndrome (AIDS). HIV seropositive individualsare initially asymptomatic but typically develop AIDS related complex(ARC) followed by AIDS. Affected individuals exhibit severeimmunosuppression which makes them highly susceptible to debilitatingand ultimately fatal opportunistic infections. Replication of HIV by ahost cell requires integration of the viral genome into the host cell'sDNA. Since HIV is a retrovirus, the HIV replication cycle requirestranscription of the viral RNA genome into DNA via an enzyme known asreverse transcriptase (RT).

Reverse transcriptase has three known enzymatic functions: The enzymeacts as an RNA-dependent DNA polymerase, as a ribonuclease, and as aDNA-dependent DNA polymerase. In its role as an RNA-dependent DNApolymerase, RT transcribes a single-stranded DNA copy of the viral RNA.As a ribonuclease, RT destroys the original viral RNA and frees the DNAjust produced from the original RNA. During the viral RNA-dependentpolymerization process, RT's ribonuclease activity is required forremoving RNA and leaving the polypurine tract preserved for initiationof DNA-dependent polymerization. As a DNA-dependent DNA polymerase, RTmakes a second, complementary DNA strand using the first DNA strand as atemplate. The two strands form double-stranded DNA, which is integratedinto the host cell's genome by HIV integrase.

It is known that compounds that inhibit enzymatic functions of HIV RTwill inhibit HIV replication in infected cells. These compounds areuseful in the treatment of HIV infection in humans. There are twoclasses of RT inhibitors: one is non-nucleoside active site competitiveRT inhibitors (NNRTIs), such as efavirenz (EFV), nevirapine (NVP),etravirine (ETR), and rilpivirine (RPV), and the other is active site RTinhibitors which include nucleoside reverse transcriptase inhibitors(NsRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs)collectively referred to as NRTIs. Examples of NsRTI's include3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxycytidine (ddC), 2′,3′-didehydro-2′,3′-dideoxythymidine(d4T), 2′,3′-dideoxy-3′-thiacytidine (3TC), abacavir, and emtricitabine.Examples of NtRTIs include tenofovir (TFV, also known as PMPA,9-(2-phosphonyl-methoxypropyl)adenine), tenofovir disoproxil fumarate(VIREAD®, U.S. Pat. No. 5,977,089, U.S. Pat. No. 5,935,946) andtenofovir alafenamide fumarate (U.S. Pat. Nos. 7,390,791, 8,754,065).

TFV belongs to a class of HIV anti-retroviral (ARV) agents known asnucleotide analog reverse transcriptase inhibitors (NRTIs). Tenofovir isa monophosphonate:

After being taken up by cells, TFV is first converted totenofovir-monophosphate (TFV-MP) by adenosine monophosphate kinase andthen to the active antiviral tenofovir-diphosphate (TFV-DP) by5′-nucleoside diphosphate kinase.

TFV-DP inhibits HIV DNA synthesis by competing with the naturalsubstrate, deoxyadenosine triphosphate, for incorporation into thecomplementary DNA strand by HIV reverse transcriptase; followingincorporation, TFV acts as a chain terminator due to lack of a3′-hydroxyl group that is required for addition of the next nucleotide.TFV has poor cellular permeability and thus has limited bioavailability.Tenofovir disoproxil fumarate (TDF) is approved for treating HIVinfection and is marketed by Gilead under the trade name VIREAD™. Thedisoproxil prodrug improves cell permeability and absorption after oraldosing, with the pro-moiety being cleaved rapidly after absorption toyield the parent TFV. As a result, the circulating level of TFV is muchhigher than that of TDF. Tenofovir alafenamide fumarate (TAF) iscurrently approved by the USFDA as an active ingredient in combinationwith additional ARVs for treating HIV infection in the pharmaceuticalproducts GENVOYA®, ODEFSEY® and DESCOVY®.

While each of the foregoing drugs is effective in treating HIV infectionand AIDS, there remains a need to develop additional HIV antiviral drugsincluding additional RT inhibitors. A particular problem is thedevelopment of mutant HIV strains that are resistant to the knowninhibitors. The use of RT inhibitors to treat AIDS often leads toviruses that are less sensitive to the inhibitors. This resistance istypically the result of mutations that occur in the reversetranscriptase segment of the pol gene. The continued use of antiviralcompounds to prevent HIV infection will inevitably result in theemergence of new resistant strains of HIV. Accordingly, there is aparticular need for new RT inhibitors that are effective against mutantHIV strains.

SUMMARY OF THE INVENTION

The present invention is directed to beta-amino acid esterphosphodiamide prodrugs of tenofovir and their use in the inhibition ofnucleotide reverse transcriptase. In addition to the use of saidcompounds in the inhibition of HIV reverse transcriptase, the inventionis also directed to the use of said compounds for prophylaxis ofinfection by HIV, the treatment of infection by HIV, and theprophylaxis, treatment, and/or delay in the onset or progression of AIDSand/or ARC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of structural Formula I:

or pharmaceutically acceptable salt thereof, wherein:

-   R¹ and R² are each independently selected from (a) H, (b)    —C₁₋₄alkyl, (c) —C₁₋₄alkyl substituted with —OH, —SH, —SCH₃, —NH₂ or    —NH—C(═NH)—NH₂, (d) —CH₂-phenyl, (e) —CH₂-phenol, (f)    —(CH₂)₁₋₂—COOH, (g) —(CH₂)₁₋₂—CONH₂, (h) —CH₂-1H-indole, (i)    —CH₂-imidazole, (j) aryl (for example but not limited to phenyl or    naphthyl) or (k) heteroaryl (for example but not limited to    pyridine);-   R³ is    -   (a) —C₁₋₁₀alkyl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(10a), —SH, —NR¹¹R¹², —C₃₋₆cycloalkyl or        spiro-C₃₋₆cycloalkyl,    -   (b) —CH₂-phenyl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,    -   (c) —C₃₋₈cycloalkyl unsubstituted or substituted with one to        three substituents independently selected from fluoro, chloro,        bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,    -   (d) aryl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,    -   (e) —C₁₋₅alkyl-X—C₁₋₅alkyl wherein X is O, S or NH,    -   (f) heteroaryl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, or    -   (g) a heterocyclic ring unsubstituted or substituted with one to        three substituents independently selected from fluoro, chloro,        bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl;-   R^(A) is an L-amino acid ester residue of formula (i), a D-amino    acid ester residue of formula (ii), a glycine ester residue of    formula (iii), a geminally di-substituted amino acid ester residue    of formula (iv), a beta amino acid ester residue of formula (v), or    an L-proline ester residue of formula (vi):

-   R⁴ is (a) —C₁₋₄alkyl, (b) —C₁₋₄alkyl substituted with —OH, —SH,    —SCH₃, —NH₂, —NH—C(═NH)—NH₂, (c) —CH₂-phenyl, (d) —CH₂-phenol, (e)    —(CH₂)₁₋₂—COOH, (f) —(CH₂)₁₋₂—CONH₂, (g) —CH₂-1H-indole, (h)    —CH₂-imidazole, (i) aryl (for example but not limited to phenyl or    naphthyl) or (j) heteroaryl (for example but not limited to    pyridine);-   R⁵ and R⁶ are each independently selected from (a) —C₁₋₄alkyl, (b)    —C₁₋₄alkyl substituted with —OH, —SH, —SCH₃, —NH₂,    —NH—C(═NH)—NH₂, (c) —CH₂-phenyl, (d) —CH₂-phenol, (e)    —(CH₂)₁₋₂—COOH, (f) —(CH₂)₁₋₂—CONH₂, (g) —CH₂-1H-indole, (h)    —CH₂-imidazole, (i) aryl (for example but not limited to phenyl or    naphthyl) or (j) heteroaryl (for example but not limited to    pyridine);-   or R⁵ and R⁶ are joined together with the carbon to which they are    both attached to form —C₃₋₆cycloalkyl or a 4 to 6-membered    heterocyclic ring;-   R⁷ and R⁸ are each independently selected from (a) H, (b)    —C₁₋₄alkyl, (c) —C₁₋₄alkyl substituted with —OH, —SH, —SCH₃, —NH₂ or    —NH—C(═NH)—NH₂, (d) —CH₂-phenyl, (e) —CH₂-phenol, (f)    —(CH₂)₁₋₂—COOH, (g) —(CH₂)₁₋₂—CONH₂, (h) —CH₂-1H-indole, (i)    —CH₂-imidazole, (j) aryl (for example but not limited to phenyl or    naphthyl) or (k) heteroaryl (for example but not limited to    pyridine);-   R⁹ is    -   (a) —C₁₋₁₀alkyl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(10b), —SH, —NR¹³R¹⁴, —C₃₋₆cycloalkyl or        spiro-C₃₋₆cycloalkyl,    -   (b) —CH₂-phenyl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,    -   (c) —C₃₋₈cycloalkyl unsubstituted or substituted with one to        three substituents independently selected from fluoro, chloro,        bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,    -   (d) aryl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,    -   (e) —C₁₋₅alkyl-X—C₁₋₅alkyl wherein X is O, S or NH;    -   (f) heteroaryl unsubstituted or substituted with one to three        substituents independently selected from fluoro, chloro, bromo,        —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, or    -   (g) a heterocyclic ring unsubstituted or substituted with one to        three substituents independently selected from fluoro, chloro,        bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl;-   R^(10a) and R^(10b) are each independently selected from —H or    —C₃₋₆cycloalkyl;-   R¹¹ and R¹² are each independently selected from —H, —C₁₋₃alkyl or    —C₃₋₆cycloalkyl;-   R¹³ and R¹⁴ are each independently selected from —H, —C₁₋₃alkyl or    —C₃₋₆cycloalkyl, and-   R^(15a) and R^(15b) are each independently selected from —H,    —C₁₋₃alkyl or —C₃₋₆cycloalkyl.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula (i),referred to herein as compounds of Formula I-i.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula(ii), referred to herein as compounds of Formula I-ii.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula(iii), referred to herein as compounds of Formula I-iii.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula(iv), referred to herein as compounds of Formula I-iv.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula (v),referred to herein as compounds of Formula I-v.

In an embodiment of this invention are compounds of Formula I or thepharmaceutically acceptable salts thereof, wherein R^(A) is formula(vi), referred to herein as compounds of Formula I-vi.

In Embodiment 1 of this invention are compounds of Formula I, I-i, I-ii,I-iii, I-iv, I-v or I-vi, or Embodiment 2, 2a, 3, 4, 5, 6, 6a or 7, or aclass thereof, or the pharmaceutically acceptable salts thereof, whereinR¹ is H or —C₁₋₄alkyl and R² is H or —C₁₋₄alkyl. In a class thereof, oneof R¹ and R² is H, and the other is H or —C₁₋₄alkyl; and in a sub-classthereof one of R¹ and R² is H, and the other is —C₁₋₄alkyl, for examplemethyl or i-propyl.

In Embodiment 2 of this invention are compounds of Formula I, I-i, I-ii,I-iii, I-iv, I-v or I-vi or Embodiment 1, or the pharmaceuticallyacceptable salts thereof, wherein R³ is

-   (a) —C₁₋₈alkyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,    —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,-   (b) —CH₂-phenyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (c) —C₃₋₆cycloalkyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (d) phenyl or naphthyl, each unsubstituted or substituted with one    to three substituents independently selected from fluoro, chloro,    bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (e) —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃,    —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃,-   (f) pyridyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, or-   (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or    tetrahydropyranyl, each unsubstituted or substituted with one to    three substituents independently selected from fluoro, chloro,    bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl.    In a class of Embodiment 2, referred to as Embodiment 2a, R³ is    —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and    in a sub-class thereof, R³ is —C₃₋₈alkyl, for example i-propyl.

In Embodiment 3 of this invention are compounds of Formula L I-i or I-iior Embodiment 1, 2 or 2a, or the pharmaceutically acceptable saltsthereof, wherein R⁴ is —C₁₋₄alkyl and in a sub-class thereof R⁴ is —CH₃.

In Embodiment 4 of this invention are compounds of Formula I or I-iv orEmbodiment 1 or 2, or the pharmaceutically acceptable salts thereof,wherein R⁵ and R⁶ are each independently selected from —CH₃, —CH₂CH₃,—C₃alkyl or —C₄alkyl. In another class of Embodiment 4, R⁵ and R⁶ areboth the same atom moiety which is selected from —CH₃, —CH₂CH₃, —C₃alkylor —C₄alkyl; and in a sub-class thereof R⁵ and R⁶ are both —CH₃.

In Embodiment 5 of this invention are compounds of Formula I or I-v orEmbodiment 1 or 2, or the pharmaceutically acceptable salts thereof,wherein R⁷ is H or —C₁₋₄alkyl and R⁸ is H or —C₁₋₄alkyl. In a classthereof, one of R⁷ and R⁸ is H, and the other is H or —C₁₋₄alkyl.

In Embodiment 6 of this invention are compounds of Formula I, I-i, I-ii,I-iii, I-iv, I-v or I-vi or Embodiment 1, 2 or 2a, or thepharmaceutically acceptable salts thereof, wherein R⁹ is

-   (a) —C₁₋₈alkyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,    —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,-   (b) —CH₂-phenyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (c) —C₃₋₆cycloalkyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (d) phenyl or naphthyl, each unsubstituted or substituted with one    to three substituents independently selected from fluoro, chloro,    bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (e) —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃,    —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃,-   (f) pyridyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, or-   (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or    tetrahydropyranyl, each unsubstituted or substituted with one to    three substituents independently selected from fluoro, chloro,    bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl.    In a class of Embodiment 6, referred to as Embodiment 6a, R⁹ is    —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and    in a sub-class thereof, R⁹ is —C₃₋₈alkyl, cyclobutyl, cyclopentyl or    cyclohexyl.

In Embodiment 7 of this invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, wherein:

R¹ is H or —C₁₋₄alkyl;R² is H or —C₁₋₄alkyl;

R³ is

-   (a) —C₁₋₈alkyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,    —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,-   (b) —CH₂-phenyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (c) —C₃₋₆cycloalkyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (d) phenyl or naphthyl, each unsubstituted or substituted with one    to three substituents independently selected from fluoro, chloro,    bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl,-   (e) —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃,    —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃,-   (f) pyridyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, or-   (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or    tetrahydropyranyl, each unsubstituted or substituted with one to    three substituents independently selected from fluoro, chloro,    bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl;    R⁴ is —C₁₋₄alkyl;    R⁵ and R⁶ are both the same moiety which is selected from —CH₃,    —CH₂CH₃, —C₃alkyl or —C₄alkyl;    R⁷ is H or —C₁₋₄alkyl and R⁸ is H or —C₁₋₄alkyl;

R⁹ is

-   (a) —C₁₋₈alkyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,    —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,-   (b) —CH₂-phenyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (c) —C₃₋₆cycloalkyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (d) phenyl or naphthyl, each unsubstituted or substituted with one    to three substituents independently selected from fluoro, chloro,    bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl,-   (e) —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃,    —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃,-   (f) pyridyl, unsubstituted or substituted with one to three    substituents independently selected from fluoro, chloro, bromo,    —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, or-   (g) piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or    tetrahydropyranyl, each unsubstituted or substituted with one to    three substituents independently selected from fluoro, chloro,    bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl;    and the remaining variables are as defined in Formula I.

In Embodiment 8 of this invention are compounds of Formula I, I-i, I-ii,I-iii, I-iv, I-v or I-vi, or a pharmaceutically acceptable salt thereof,wherein

one of R¹ and R² is H, and the other is —C₁₋₄alkyl; andR³ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,or R³ is i-propyl.

In Embodiment 9 of this invention are compounds of Embodiment 8 havingFormula I or I-i, or a pharmaceutically acceptable salt thereof, wherein

R⁴ is —C₁₋₄alkyl or R⁴ is methyl; andR⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, orR⁹ is —C₃₋₈alkyl.

In Embodiment 10 of this invention are compounds of Embodiment 8 havingFormula I or I-ii, or a pharmaceutically acceptable salt thereof,wherein

R⁴ is —C₁₋₄alkyl or R⁴ is methyl; andR⁹ —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or R⁹is —C₃₋₈alkyl.

In Embodiment 11 of this invention are compounds of Embodiment 8 havingFormula I or I-iii, or a pharmaceutically acceptable salt thereof,wherein

R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, orR⁹ is —C₃₋₈alkyl.

In Embodiment 12 of this invention are compounds of Embodiment 8 havingFormula I or I-iv, or a pharmaceutically acceptable salt thereof,wherein

R⁵ and R⁶ are both the same atom moiety which is selected from —CH₃,—CH₂CH₃, —C₃alkyl or —C₄alkyl, or R⁵ and R⁶ are both —CH₃; andR⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, orR⁹ is —C₃₋₈alkyl.

In Embodiment 13 of this invention are compounds of Formula I or I-v, ora pharmaceutically acceptable salt thereof, wherein

R¹ is H or —C₁₋₄alkyl; R² is H or —C₁₋₄alkyl;R⁷ is H or —C₁₋₄alkyl; R⁸ is H or —C₁₋₄alkyl;R³ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,or R³ is i-propyl; andR⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, orR⁹ is —C₃₋₈alkyl.

In Embodiment 14 of this invention are compounds of Embodiment 8 havingFormula I or I-vi, or a pharmaceutically acceptable salt thereof,wherein R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, or R⁹ is —C₃₋₈alkyl.

In Embodiment 15 of this invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, wherein:

one of R¹ and R² is H, and the other is H or —C₁₋₄alkyl;R³ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;R⁴ is —CH₃;R⁵ and R⁶ are both —CH₃;R⁷ is H or —C₁₋₄alkyl; R⁸ is H or —C₁₋₄alkyl;R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;and the remaining variables are as defined in Formula I.

In Embodiment 16 of this invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, wherein:

one of R¹ and R² is H, and the other is methyl or i-propyl;R³ is —C₃₋₈alkyl, or R³ is i-propyl;R⁴ is —CH₃;R⁵ and R⁶ are both —CH₃;R⁷ is H or —C₁₋₄alkyl; R⁸ is H or —C₁₋₄alkyl; andR⁹ is —C₃₋₈alkyl, cyclobutyl, cyclopentyl or cyclohexyl;and the remaining variables are as defined in Formula I.

Reference to the compounds of Formula I herein encompasses the compoundsof Formula I and all embodiments, classes and sub-classes thereof. Thecompounds of the invention encompass compounds of Formula I and saltsthereof when such salts are possible, including pharmaceuticallyacceptable salts.

As used herein, “alkyl” refers to both branched- and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms in a specified range. For example the term “C₁₋₁₀ alkyl”means linear or branched chain alkyl groups, including all possibleisomers, having 1, 2, 3, 4, 5, 7, 8, 9 or 10 carbon atoms, and includeseach of the decyl, nonyl, octyl, heptyl, hexyl and pentyl isomers aswell as n-, iso-, sec- and tert-butyl (butyl, s-butyl, i-butyl, t-butyl;Bu=butyl, collectively “—C₄alkyl”), n- and iso-propyl (propyl, i-propyl,Pr=propyl, collectively “—C₃alkyl”), ethyl (Et) and methyl (Me).“C₁₋₄alkyl” has 1, 2, 3 or 4 carbon atoms, and includes each of n-,iso-, sec- and tert-butyl, n- and i-propyl, ethyl and methyl.

“Cycloalkyl” refers to a cyclized alkyl ring having the indicated numberof carbon atoms in a specified range. Thus, for example, “C₃₋₈cycloalkyl” encompasses each of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyloheptyl and cyclooctyl. “C₃₋₆cycloalkyl” encompasses eachof cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When cycloalkylis a substituent on an alkyl group in a compound of Formula I, thecycloalkyl substituent can be bonded to any available carbon in thealkyl group. The following are illustrations of —C₃₋₆cycloalkylsubstituents wherein the substituent is cyclopropyl in bold:

“Spiro-C₃₋₆cycloalkyl” refers to a cycloalkyl ring bonded to anon-terminal carbon atom wherein the non-terminal carbon atom is sharedwith the cycloalkyl group. Spiro-C₃₋₆cycloalkyl encompasses each ofspiro-cyclopropyl, spiro-cyclobutyl, spiro-cyclopentyl andspiro-cyclohexyl. The following is an illustration of aspiro-C₃₋₆cycloalkyl substituent wherein the substituent isspiro-cyclopropyl in bold:

Examples of —C₁₋₅alkyl-X—C₁₋₅alkyl groups include, but are not limitedto, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃,—CH₂CH₂NHCH₃ or —CH₂CH₂CH₂NHCH₃.

“Aryl” refers to (i) phenyl, (ii) 9- or 10-membered bicyclic, fusedcarbocylic ring systems in which at least one ring is aromatic, and(iii) 11- to 14-membered tricyclic, fused carbocyclic ring systems inwhich at least one ring is aromatic. Suitable aryls include, forexample, substituted and unsubstituted phenyl and substituted andunsubstituted naphthyl. An aryl of particular interest is unsubstitutedor substituted phenyl.

“Heteroaryl” refers to (i) a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, wherein each N is optionally in the form of an oxide, and (ii) a 9-or 10-membered bicyclic fused ring system, wherein the fused ring systemof (ii) contains from 1 to 6 heteroatoms independently selected from N,O and S, wherein each ring in the fused ring system contains zero, oneor more than one heteroatom, at least one ring is aromatic, each N isoptionally in the form of an oxide, and each S in a ring which is notaromatic is optionally S(O) or S(O)₂. Suitable 5- and 6-memberedheteroaromatic rings include, for example, pyridyl, 3-fluroropyridyl,4-fluoropyridyl, 3-methoxypyridyl, 4-methoxypyridyl, pyrrolyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl,imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or1,2,4-triazolyl), tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl (i.e.,the 1,2,3-, 1,2,4-, 1,2,5- (furazanyl), or 1,3,4-isomer), oxatriazolyl,thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-memberedheterobicyclic, fused ring systems include, for example, benzofuranyl,indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl,benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl,isoindolyl, benzopiperidinyl, benzofuranyl, imidazo[1,2-a]pyridinyl,benzotriazolyl, indazolyl, indolinyl, and isoindolinyl. A class ofheteroaryls includes unsubstituted or substituted pyridyl or pyrimidyl,and particularly unsubstituted or substituted pyridyl.

The term “heterocyclic ring” refers to (i) a saturated 4- to 7-memberedcyclized ring and (ii) an unsaturated, non-aromatic 4 to 7-memberedcyclized ring comprised of carbon atoms and 1-4 heteratoms independentlyselected from O, N and S. Heterocyclic rings within the scope of thisinvention include, for example, azetidinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl,hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4-to 7-membered, unsaturated, non-aromatic heterocyclic rings within thescope of this invention include mono-unsaturated heterocyclic ringscorresponding to the saturated heterocyclic rings listed in thepreceding sentence in which a single bond is replaced with a double bond(e.g., a carbon-carbon single bond is replaced with a carbon-carbondouble bond). A class of heterocyclic rings are 4 to 6-memberedsaturated monocyclic rings comprised of carbon atoms and 1 or 2heteroatoms, wherein the heteroatoms are selected from N, O and S.Examples of 4 to 6 membered heterocyclic rings include but are notlimited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl andtetrahydrothiopyranyl, and a sub-class thereof is piperidinyl,pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl. The following isan illustration of R⁵ and R⁶ when they are joined together to form aheterocyclic ring:

With respect to substituents on a molecule, “geminally” or “geminal”refers to two substituents, which may be the same or different, on onecarbon.

It is understood that the specific rings and ring systems suitable foruse in the present invention are not limited to those listed in thepreceding paragraphs. These rings and ring systems are merelyrepresentative.

As would be recognized by one of ordinary skill in the art, certaincompounds of the present invention may be able to exist as tautomers.All tautomeric forms of these compounds, whether isolated individuallyor in mixtures, are within the scope of the present invention. Forexample, in instances where an —OH substituent is permitted on aheteroaromatic ring and keto-enol tautomerism is possible, it isunderstood that the substituent might in fact be present, in whole or inpart, in the oxo (═O) form.

A “stable” compound is a compound which can be prepared and isolated andwhose structure and properties remain or can be caused to remainessentially unchanged for a period of time sufficient to allow use ofthe compound for the purposes described herein (e.g., therapeutic orprophylactic administration to a subject). The compounds of the presentinvention are limited to stable compounds embraced by Formula I and itsembodiments. For example, certain moieties as defined in Formula I maybe unsubstituted or substituted, and the latter is intended to encompasssubstitution patterns (i.e., number and kind of substituents) that arechemically possible for the moiety and that result in a stable compound.

Each compound of Formula I is comprised of a phosphodiamide amino acidester having a defined (R) chiral center in the alkyl-ether linkinggroup connecting the nucleobase to the phosphodiamide as shown inFormula I, and may have one or more additional chiral centers dependingon substituent selection. For example, each of Examples 6-28 herein alsohas an assymetric phosphorus center. Accordingly, a compound of FormulaI may have multiple chiral centers (also referred to as asymmetric orstereogenic centers. This invention encompasses compounds having eitherthe (R) or (S) stereo-configuration at a phosphorus assymetric centerand at any additional assymetric centers that may be present in acompound of Formula I, as well as stereo-isomeric mixtures thereof.

This invention includes individual diastereomers, particularly epimers,i.e., compounds having the same chemical formula but which differ in thespatial arrangement around a single atom. This invention also includesmixtures of diastereomers, particularly mixtures of epimers, in allratios. Embodiments of this invention also include a mixture of epimersenriched with 51% or more of one of the epimers, including for example60% or more, 70% or more, 80% or more, or 90° %, or more of one epimer.A single epimer is preferred. An individual or single epimer refers toan epimer obtained by chiral synthesis and/or using generally knownseparation and purification techniques, and which may be 100% of oneepimer or may contain small amounts (e.g., 10% or less) of the oppositeepimer. Thus, individual diasteromers are a subject of the invention inpure form, both as levorotatory and as dextrorotatory antipodes, in theform of racemates and in the form of mixtures of the two diasteromers inall ratios. In the case of a cis/trans isomerism the invention includesboth the cis form and the trans form as well as mixtures of these formsin all ratios.

The preparation of individual stereoisomers can be carried out, ifdesired, by separation of a mixture by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials for the synthesis or by stereoselectivesynthesis. Optionally a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at an intermediate step during thesynthesis of a compound of Formula I or it can be done on a finalracemic product. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing astereogenic center of known configuration. Alternatively, absolutestereochemistry may be determined by Vibrational Circular Dichroism(VCD) spectroscopy analysis. The present invention includes all suchisomers, as well as salts, solvates (which includes hydrates) andsolvated salts of such racemates, enantiomers, diastereomers andtautomers and mixtures thereof.

The atoms in a compound of Formula I may exhibit their natural isotopicabundances, or one or more of the atoms may be artificially enriched ina particular isotope having the same atomic number, but an atomic massor mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formula I; forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof Formula I can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

The compounds can be administered in the form of pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt” refers toa salt which is not biologically or otherwise undesirable (e.g., isneither toxic nor otherwise deleterious to the recipient thereof). Sincethe compounds of Formula I contain by definition at least one basicgroup, the invention includes the corresponding pharmaceuticallyacceptable salts. When the compounds of Formula I contain one or moreacidic groups, the invention also includes the correspondingpharmaceutically acceptable salts. Thus, the compounds of Formula I thatcontain acidic groups (e.g., —COOH) can be used according to theinvention as, for example but not limited to, alkali metal salts,alkaline earth metal salts or as ammonium salts. Examples of such saltsinclude but are not limited to sodium salts, potassium salts, calciumsalts, magnesium salts or salts with ammonia or organic amines such as,for example, ethylamine, ethanolamine, triethanolamine or amino acids.Compounds of Formula I, which contain one or more basic groups, i.e.groups which can be protonated, can be used according to the inventionin the form of their acid addition salts with inorganic or organic acidsas, for example but not limited to, salts with hydrogen chloride,hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid,benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroaceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofFormula I simultaneously contain acidic and basic groups in the moleculethe invention also includes, in addition to the salt forms mentioned,inner salts or betaines (zwitterions). Salts can be obtained from thecompounds of Formula I by customary methods which are known to theperson skilled in the art, for example by combination with an organic orinorganic acid or base in a solvent or dispersant, or by anion exchangeor cation exchange from other salts. The present invention also includesall salts of the compounds of Formula I which, owing to lowphysiological compatibility, are not directly suitable for use inpharmaceuticals but which can be used, for example, as intermediates forchemical reactions or for the preparation of pharmaceutically acceptablesalts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula I areintended to be included within the scope of the present invention. Inaddition, some of the compounds of the instant invention may formsolvates with water (i.e., a hydrate) or common organic solvents. Suchsolvates and hydrates, particularly the pharmaceutically acceptablesolvates and hydrates, of the compounds of this invention are likewiseencompassed within the scope of the compounds defined by Formula I andthe pharmaceutically acceptable salts thereof, along with un-solvatedand anhydrous forms of such compounds.

The instant invention encompasses any composition comprised of acompound of Formula I or a compound that is a salt thereof, includingfor example but not limited to, a composition comprised of said compoundassociated together with one or more additional molecular and/or ioniccomponent(s) which may be referred to as a “co-crystal.” The term“co-crystal” as used herein refers to a solid phase (which may or maynot be crystalline) wherein two or more different molecular and/or ioniccomponents (generally in a stoichiometric ratio) are held together bynon-ionic interactions including but not limited to hydrogen-bonding,dipole-dipole interactions, dipole-quadrupole interactions or dispersionforces (van der Waals). There is no proton transfer between thedissimilar components and the solid phase is neither a simple salt nor asolvate. A discussion of co-crystals can be found, e.g., in S.Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp.2147-2152.

More specifically with reference to this invention, a co-crystal iscomprised of a compound of Formula I or a pharmaceutically acceptablesalt thereof, and one or more non-pharmaceutically active component(s)which is not biologically or otherwise undesirable (e.g., is neithertoxic nor otherwise deleterious to the recipient thereof). Co-crystalscan be obtained from a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, by customary methods known in the chemicalarts. For example, co-crystals comprised of a compound of this inventioncould be prepared by adding an acid or a neutral molecule at the desiredstoichiometry to the compound, adding an appropriate solvent to achievedissolution and, for example, precipitating, lyophilizing orconcentrating the solution to obtain the solid composition. Theco-crystal can be, but is not limited to, an embodiment wherein thecomposition is comprised of a neutral compound (i.e. not a salt form) ofFormula I and one or more non-pharmaceutically active component(s); andin a further embodiment, the co-crystal composition is crystalline.Crystalline compositions may be prepared, for example, by adding an acidor a neutral molecule at the desired stoichiometry to the compound ofFormula I, adding an appropriate solvent and heating to achieve completedissolution, and then allowing the solution to cool and the crystals togrow. The present invention also includes all co-crystals of thecompounds of this invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable co-crystals orsalts.

Accordingly, the compounds of Formula I, embodiments thereof andspecific compounds described and claimed herein encompass all possiblepharmaceutically acceptable salts, stereoisomers, tautomers, physicalforms (e.g., amorphous and crystalline forms), co-crystal compositions,solvate and hydrate forms and any combination of the foregoing formswhere such forms are possible.

The compounds of Formula I described herein are prodrugs. A discussionof prodrugs is provided in (a) Stella, V. J.; Borchardt, R. T.; Hageman,M. J.; Oliyai, R.; Maag, H. et al. Prodrugs: Challenges and Rewards Part1 and Part 2; Springer, p. 726: New York, N.Y., USA, 2007, (b) Rautio,J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D. et al. Prodrugs:design and clinical applications. Nat. Rev. Drug Discov. 2008, 7, 255,(c) T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987)14 of the A.C.S. Symposium Series, and in (d) Bioreversible Carriers inDrug Design, (1987) Edward B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press. More specifically, compounds of FormulaI (or any embodiment thereof and pharmaceutically acceptable saltsthereof) are prodrug modifications of tenofovir, which is amono-phosphonate. The compounds of Formula I may be convertedintracellularly (in vivo or in vitro) to the corresponding monophosphateor diphosphate of tenofovir. The conversion may occur by one or moremechanisms, e.g., an enzyme-catalyzed chemical reaction, a metabolicchemical reaction, and/or a spontaneous chemical reaction (e.g.,solvolysis), such as, for example, through hydrolysis in blood. Whilenot wishing to be bound by any particular theory, tenofovir diphosphateis generally understood to be responsible for inhibiting the HIV RTenzyme and for the resulting antiviral activity after administration ofthe compound of Formula I to a subject.

Another embodiment of the present invention is a compound of Formula Iwherein the compound or its salt is in a substantially pure form. Asused herein “substantially pure” means suitably at least about 60 wt. %,typically at least about 70 wt. %, preferably at least about 80 wt. %,more preferably at least about 90 wt. % (e.g., from about 90 wt. % toabout 99 wt. %), even more preferably at least about 95 wt. % (e.g.,from about 95 wt. % to about 99 wt. %, or from about 98 wt. % to 100 wt.%), and most preferably at least about 99 wt. % (e.g., 100 wt. %) of aproduct containing a compound of Formula I or its salt (e.g., theproduct isolated from a reaction mixture affording the compound or salt)consists of the compound or salt. The level of purity of the compoundsand salts can be determined using a standard method of analysis such as,high performance liquid chromatography, and/or mass spectrometry or NMRtechniques. If more than one method of analysis is employed and themethods provide experimentally significant differences in the level ofpurity determined, then the method providing the highest purity levelgoverns. A compound or salt of 100% purity is one which is free ofdetectable impurities as determined by a standard method of analysis.With respect to a compound of the invention which has one or moreasymmetric centers and can occur as mixtures of stereoisomers, asubstantially pure compound can be either a substantially pure mixtureof the stereoisomers or a substantially pure individual stereoisomer.

The compounds of Formula I herein, and pharmaceutically acceptable saltsthereof, are useful for HIV reverse transcriptase inhibition and forinhibiting HIV replication in vitro and in vivo. More particularly, thecompounds of Formula I for inhibiting the polymerase function of HIV-1reverse transcriptase. The testing of compounds of the Examples of thisinvention in the Viking assay set forth in Example 29 below, illustratethe ability of compounds of the invention to inhibit the RNA-dependentDNA polymerase activity of HIV-1 reverse transcriptase. The compounds ofFormula I may also be useful agents against HIV-2. The compounds ofExamples 1-28 (inclusive of A and B isomers) of the present inventionalso exhibit activity against drug resistant forms of HIV (e.g.,NNRTI-associated mutant strains K103N and/or Y181C; NRTI-associatedmutant strains M184V and M184I mutants). This invention also encompassesmethods for the treatment or prophylaxis of infection by HIV, for theinhibition of HIV reverse transcriptase, for the treatment, prophylaxis,or delay in the onset of AIDS in a subject in need thereof, whichcomprise administering to the subject an effective amount of a compoundof the invention or a pharmaceutically acceptable salt thereof.

The invention further encompasses methods for the treatment orprophylaxis of infection by HIV, for the inhibition of HIV reversetranscriptase, for the treatment, prophylaxis, or delay in the onset ofAIDS in a subject in need thereof, which comprise administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof in combination with aneffective amount of one or more additional anti-HIV agents selected fromthe group consisting of HIV antiviral agents, immunomodulators, andanti-infective agents. Within this embodiment, the anti-HIV agent is anantiviral selected from the group consisting of HIV protease inhibitors,HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIVfusion inhibitors, HIV entry inhibitors, and HIV maturation inhibitors

The invention encompasses a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. Theinvention also encompasses a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrierfurther comprising an effective amount of one or more additionalanti-HIV agents selected from the group consisting of HIV antiviralagents, immunomodulators, and anti-infective agents. Within thisembodiment, the anti-HIV agent is an antiviral selected from the groupconsisting of HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entryinhibitors, and HIV maturation inhibitors.

The compounds of this invention could also be useful for inhibition ofHBV reverse transcriptase. Accordingly, this invention also encompassesmethods for the treatment of chronic hepatitis B which compriseadministering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

The invention also encompasses a compound of the invention, or apharmaceutically acceptable salt thereof, for use in the preparation ofa medicament for the treatment or prophylaxis of infection by HIV, forthe inhibition of HIV reverse transcriptase, or for the treatment,prophylaxis, or delay in the onset of AIDS in a subject in need thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) an effective amount of a compound of Formula Ior a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

(c) The pharmaceutical composition of (a) or (b), further comprising aneffective amount of one or more an anti-HIV agents selected from thegroup consisting of HIV antiviral agents, immunomodulators, andanti-infective agents.

(d) The pharmaceutical composition of (c), wherein the anti-HIV agent isselected from one or more of an antiviral selected from the groupconsisting of HIV protease inhibitors, nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entryinhibitors and HIV maturation inhibitors.

(e) A combination which is (i) a compound of Formula I or apharmaceutically acceptable salt thereof and (ii) an anti-HIV agentselected from the group consisting of HIV antiviral agents,immunomodulators, and anti-infective agents; wherein the compound andthe anti-HIV agent are each employed in an amount that renders thecombination effective for inhibition of HIV reverse transcriptase, fortreatment or prophylaxis of infection by HIV, or for treatment,prophylaxis of, or delay in the onset or progression of AIDS.

(f) The combination of (e), wherein the anti-HIV agent is an antiviralselected from the group consisting of HIV protease inhibitors,nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusioninhibitors, HIV entry inhibitors and HIV maturation inhibitors.

(g) A method for the inhibition of HIV reverse transcriptase in asubject in need thereof which comprises administering to the subject aneffective amount of a compound of Formula I or pharmaceuticallyacceptable salt thereof.

(h) A method for the prophylaxis or treatment of infection by HIV (e.g.,HIV-1) in a subject in need thereof which comprises administering to thesubject an effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof.

(i) The method of (h), wherein the compound of Formula I or apharmaceutically acceptable salt thereof is administered in combinationwith an effective amount of at least one other HIV antiviral selectedfrom the group consisting of HIV protease inhibitors, HIV integraseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors,nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors,HIV entry inhibitors and HIV maturation inhibitors.

(j) A method for the prophylaxis, treatment or delay in the onset orprogression of AIDS in a subject in need thereof which comprisesadministering to the subject an effective amount of a compound ofFormula I or pharmaceutically acceptable salt thereof.

(k) The method of (j), wherein the compound is administered incombination with an effective amount of at least one other HIV antiviralselected from the group consisting of HIV protease inhibitors, HIVintegrase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusioninhibitors, HIV entry inhibitors and HIV maturation inhibitors.

(l) A method for the inhibition of HIV reverse transcriptase in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(m) A method for the prophylaxis or treatment of infection by HIV (e.g.,HIV-1) in a subject in need thereof, which comprises administering tothe subject the pharmaceutical composition of (a), (b), (c) or (d) orthe combination of (e) or (f).

(n) A method for the prophylaxis, treatment, or delay in the onset orprogression of AIDS in a subject in need thereof which comprisesadministering to the subject the pharmaceutical composition of (a), (b),(c) or (d) or the combination of (e) or (f).

The present invention also includes a compound of Formula I orpharmaceutically acceptable salt thereof (i) for use in, (ii) for use asa medicament for, or (iii) for use in the preparation of a medicamentfor: (a) therapy (e.g., of the human body), (b) medicine, (c) inhibitionof HIV reverse transcriptase, (d) treatment or prophylaxis of infectionby HIV, or (e) treatment, prophylaxis of, or delay in the onset orprogression of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreanti-HIV agents selected from HIV antiviral agents, anti-infectiveagents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses (i)(a)-(e) through (iii)(a)-(e) set forth in the precedingparagraph, wherein the compound of the present invention employedtherein is a compound of one of the embodiments, aspects, classes,sub-classes, or features described above. In all of these embodimentsetc., the compound may optionally be used in the form of apharmaceutically acceptable salt.

Additional embodiments of the present invention include each of thepharmaceutical compositions, combinations, methods and uses set forth inthe preceding paragraphs, wherein the compound of the present inventionor its salt employed therein is substantially pure. With respect to apharmaceutical composition comprising a compound of Formula I or itssalt and a pharmaceutically acceptable carrier and optionally one ormore excipients, it is understood that the term “substantially pure” isin reference to a compound of Formula I or its salt per se.

Still additional embodiments of the present invention include thepharmaceutical compositions, combinations and methods set forth in(a)-(n) above and the uses (i)(a)-(e) through (iii)(a)-(e) set forthabove, wherein the HIV of interest is HIV-1. Thus, for example, in thepharmaceutical composition (d), the compound of Formula I is employed inan amount effective against HIV-1 and the anti-HIV agent is an HIV-1antiviral selected from the group consisting of HIV-1 proteaseinhibitors, HIV-1 reverse transcriptase inhibitors, HIV-1 integraseinhibitors, HIV-1 fusion inhibitors, HIV-1 entry inhibitors and HIV-1maturation inhibitors. The compounds of Formula I may also be usefulagents against HIV-2.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of Formula I means providing thecompound to the individual in need of treatment or prophylaxis andincludes both self-administration and administration to the patient byanother person. When a compound is provided in combination with one ormore other active agents (e.g., antiviral agents useful for treating orprophylaxis of HIV infection or AIDS), “administration” and its variantsare each understood to include provision of the compound and otheragents at the same time or at different times. When the agents of acombination are administered at the same time, they can be administeredtogether in a single composition or they can be administered separately.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results from combining the specified ingredients. Ingredientssuitable for inclusion in a pharmaceutical composition arepharmaceutically acceptable ingredients, which means the ingredientsmust be compatible with each other and not deleterious to the recipientthereof.

The term “subject” or “patient” as used herein refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

The term “effective amount” as used herein means an amount of a compoundsufficient to inhibit HIV reverse transcriptase, inhibit HIVreplication, exert a prophylactic effect, and/or a exert a therapeuticeffect after administration. One embodiment of “effective amount” is a“therapeutically effective amount” which is an amount of a compound thatis effective for inhibiting HIV reverse transcriptase, inhibiting HIVreplication (either of the foregoing which may also be referred toherein as an “inhibition effective amount”), treating HIV infection,treating AIDS, delaying the onset of AIDS, and/or slowing progression ofARC or AIDS in a patient infected with HIV. Another embodiment of“effective amount” is a “prophylactically effective amount” which is anamount of the compound that is effective for prophylaxis of HIVinfection in a subject not infected with HIV, or prophylaxis of ARC orAIDS in an HIV-infected patient. It is understood that an effectiveamount can simultaneously be both a therapeutically effective amount,e.g., for treatment of HIV infection, and a prophylactically effectiveamount, e.g., for prevention or reduction of risk for developing AIDS.The term “preventing,” as used herein with respect to an HIV viralinfection or AIDS, refers to reducing the likelihood or severity of HIVinfection or AIDS.

In the combination therapies of the present invention, an effectiveamount can refer to each individual agent or to the combination as awhole, wherein the amounts of all agents administered in the combinationare together effective, but wherein a component agent of the combinationmay or may not be present individually in an effective amount withreference to what is considered effective for that component agent if itwere administered alone.

In the method of the present invention (i.e., inhibiting HIV reversetranscriptase, treating or prophylaxis of HIV infection, inhibiting HIVreplication, treating or prophylaxis of AIDS, delaying the onset ofAIDS, or delaying or slowing progression of AIDS), the compounds of thisinvention, optionally in the form of a salt, can be administered bymeans that produce contact of the active agent with the agent's site ofaction. They can be administered by conventional means available for usein conjunction with pharmaceuticals, either as individual therapeuticagents or in a combination of therapeutic agents. They can beadministered alone, but typically are administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice. The compounds of the invention can,for example, be administered orally (e.g., via tablet or capsule),parenterally (including subcutaneous injections, intravenous,intramuscular or intrasternal injection, or infusion techniques), byinhalation spray, or rectally, in the form of a unit dosage of apharmaceutical composition containing an effective amount of thecompound and conventional non-toxic pharmaceutically acceptablecarriers, adjuvants and vehicles. The compound could also beadministered via an implantable drug delivery device adapted to providean effective amount of the compound or a pharmaceutical composition ofthe compound over an extended period of time.

Solid preparations suitable for oral administration (e.g., powders,pills, capsules and tablets) can be prepared according to techniquesknown in the art and can employ such solid excipients as starches,sugars, kaolin, lubricants, binders, disintegrating agents and the like.Liquid preparations suitable for oral administration (e.g., suspensions,syrups, elixirs and the like) can be prepared according to techniquesknown in the art and can employ any of the usual media such as water,glycols, oils, alcohols and the like. Parenteral compositions can beprepared according to techniques known in the art and typically employsterile water as a carrier and optionally other ingredients, such as asolubility aid. Injectable solutions can be prepared according tomethods known in the art wherein the carrier comprises a salinesolution, a glucose solution or a solution containing a mixture ofsaline and glucose. Implantable compositions can be prepared accordingto methods known in the art wherein the carrier comprises the activechemical ingredient with polymers as suitable excipients, or utilizingan implantable device for drug delivery. Further description of methodssuitable for use in preparing pharmaceutical compositions for use in thepresent invention and of ingredients suitable for use in saidcompositions is provided in Remington's Pharmaceutical Sciences, 18thedition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and inRemington—The Science and Practice of Pharmacy, 22nd Edition, publishedby Pharmaceutical Press and Philadelphia College of Pharmacy atUniversity of the Sciences, 2012, ISBN 978 0 85711-062-6 and prioreditions.

Formulations of compounds described by Formula I that result in drugsupersaturation and/or rapid dissolution may be utilized to facilitateoral drug absorption. Formulation approaches to cause drugsupersaturation and/or rapid dissolution include, but are not limitedto, nanoparticulate systems, amorphous systems, solid solutions, soliddispersions, and lipid systems. Such formulation approaches andtechniques for preparing them are well known in the art. For example,solid dispersions can be prepared using excipients and processes asdescribed in reviews (e.g., A. T. M. Serajuddin, J Pharm Sci, 88:10, pp.1058-1066 (1999)). Nanoparticulate systems based on both attrition anddirect synthesis have also been described in reviews such as Wu et al(F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7pp. 631-644 (2007)).

The compounds of Formula I can be administered in a dosage range of0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day, or atlonger time intervals on non-consecutive days as appropriate, in asingle dose or in divided doses. One example of a dosage range is 0.01to 500 mg/kg body weight per day, or at other time intervals asappropriate, administered orally or via other routes of administrationin a single dose or in divided doses. Another example of a dosage rangeis 0.1 to 100 mg/kg body weight per day, or at other time intervals asappropriate, administered orally or via other routes of administrationin single or divided doses. Another example of a dosage range is 50 mgto 1 gram per day, in a single dose or divided doses. When the compoundof Formula I is administered as a salt, reference to an amount of thecompound in milligrams or grams is based on the free form (i.e., thenon-salt form) of the compound. Daily or weekly administration can bevia any suitable route of administration but is preferably via oraladministration and can be a single dose or more than one dose atstaggered times (divided daily doses) within each 24 hour period,whether the dosing regimen is daily or once-weekly. Each dose may beadministered using one or multiple dosage units as appropriate.

For weekly or less frequent dosing regimens with longer time intervalson non-consecutive days, a parenteral route of administration may beemployed. Examples of such dosing regimens with longer time intervals onnon-consecutive days include but are not limited to administration onceweekly, once bi-weekly (once every two weeks with leeway as to exactdate of dosing), once monthly (e.g., once every 30 days, or the samecalendar day each month with leeway as to exact date of dosing), oncebimonthly (e.g., once every 60 days, or the same calendar day every twomonths with leeway as to exact date of dosing), once every 3 months(e.g., once every 90 days, or the same calendar day every three monthswith leeway as to exact date of dosing), once every six months (e.g.,once every 180 days, or the same calendar day every six months withleeway as to exact date of dosing), or once yearly (e.g., once every 12months with leeway as to exact date of the annual dosing). For oral(e.g., tablets or capsules) or other routes of administration, thedosage units may contain 1.0 mg to 1000 mg of the active ingredient, forexample but not limited to, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200,250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. Furthermore, the compound may be formulatedin oral formulations for immediate or modified release such as extendedor controlled release.

The favorable pharmacokinetic profile of tested compounds of thisinvention may also render the compounds suitable for less frequentdosing. Thus, the compounds of the invention could be administeredorally, weekly or parenterally at longer time intervals as describedabove. For parenteral administration, the compositions can beadministered, e.g., intravenously (IV) or intramuscularly (IM) viainjection, or using other infusion techniques. One or more of suchinjections or infusions may be administered at each dosing time intervalas needed to deliver the appropriate amount of active agent. Thecompound could also be administered subcutaneously using an implantabledevice. For parenteral administration including implantable devicesemploying longer duration dosing intervals such as once monthly, onceevery 3 months, once every 6 months, once yearly or longer intervals,the dosage amount would be adjusted upward as needed to provideeffective treatment during the time intervals between administration ofeach dose.

The specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the host undergoing therapy. In some cases, depending on the potencyof the compound or the individual response, it may be necessary todeviate upwards or downwards from the given dose. The amount andfrequency of administration will be regulated according to the judgmentof the attending clinician considering such factors.

As noted above, the present invention is also directed to use of acompound of Formula I with one or more anti-HIV agents. An “anti-HIVagent” is any agent which is directly or indirectly effective in theinhibition of HIV, the treatment or prophylaxis of HIV infection, and/orthe treatment, prophylaxis or delay in the onset or progression of AIDS.It is understood that an anti-HIV agent is effective in treating,preventing, or delaying the onset or progression of HIV infection orAIDS and/or diseases or conditions arising therefrom or associatedtherewith. For example, the compounds of this invention may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of one or moreanti-HIV agents selected from HIV antiviral agents, immunomodulators,antiinfectives, or vaccines useful for treating HIV infection or AIDS.Suitable HIV antivirals for use in combination with the compounds of thepresent invention include, for example, those listed in Table A asfollows:

TABLE A Antiviral Agents for Treating HIV infection or AIDS Name Typeabacavir, ABC, Ziagen ® nRTI abacavir + lamivudine, Epzicom ® nRTIabacavir + lamivudine + zidovudine, Trizivir ® nRTI amprenavir,Agenerase ® PI atazanavir, Reyataz ® PI AZT, zidovudine, azidothymidine,Retrovir ® nRTI capravirine nnRTI darunavir, Prezista ® PI ddC,zalcitabine, dideoxycytidine, Hivid ® nRTI ddI, didanosine,dideoxyinosine, Videx ® nRTI ddI (enteric coated), Videx EC ® nRTIdelavirdine, DLV, Rescriptor ® nnRTI dolutegravir, Tivicay ® InIdoravirine, MK-1439 nnRTI efavirenz, EFV, Sustiva ®, Stocrin ® nnRTIefavirenz + emtricitabine + tenofovir DF, Atripla ® nnRTI + nRTI EFdA(4′-ethynyl-2-fluoro-2′-deoxyadenosine) nRTI Elvitegravir InIemtricitabine, FTC, Emtriva ® nRTI emtricitabine + tenofovir DF,Truvada ® nRTI emvirine, Coactinon ® nnRTI enfuvirtide, Fuzeon ® FIenteric coated didanosine, Videx EC ® nRTI etravirine, TMC-125 nnRTIfosamprenavir calcium, Lexiva ® PI indinavir, Crixivan ® PI lamivudine,3TC, Epivir ® nRTI lamivudine + zidovudine, Combivir ® nRTI lopinavir PIlopinavir + ritonavir, Kaletra ® PI maraviroc, Selzentry ® EInelfinavir, Viracept ® PI nevirapine, NVP, Viramune ® nnRTI PPL-100(also known as PL-462) (Ambrilia) PI raltegravir, MK-0518, Isentress ™InI Rilpivirine nnRTI ritonavir, Norvir ® PI saquinavir, Invirase ®,Fortovase ® PI stavudine, d4T, didehydrodeoxythymidine, Zerit ® nRTItipranavir, Aptivus ® PI vicriviroc EI EI = entry inhibitor; FI = fusioninhibitor; InI = integrase inhibitor; PI = protease inhibitor; nRTI =nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleosidereverse transcriptase inhibitor. Some of the drugs listed in the tableare used in a salt form; e.g., abacavir sulfate, delavirdine mesylate,indinavir sulfate, atazanavir sulfate, nelfinavir mesylate, saquinavirmesylate.

It is understood that the scope of combinations of the compounds of thisinvention with anti-HIV agents is not limited to the HIV antiviralslisted in Table A, but includes in principle any combination with anypharmaceutical composition useful for the treatment or prophylaxis ofAIDS. The HIV antiviral agents and other agents will typically beemployed in these combinations in their conventional dosage ranges andregimens as reported in the art, including, for example, the dosagesdescribed in the Physicians' Desk Reference, Thomson PDR, Thomson PDR,57th edition (2003), the 58th edition (2004), or the 59th edition (2005)and the current Physicians' Desk Reference (68th ed.). (2014), Montvale,N.J.: PDR Network. The dosage ranges for a compound of the invention inthese combinations can be the same as those set forth above.

The compounds of this invention are also useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVreverse transcriptase, e.g., by competitive inhibition.

Abbreviations and acronyms employed herein include the following:

Ac acetyl ACN acetonitrile AcOH or HOAc acetic acid APCIatmospheric-pressure chemical ionization aq aqueous Bn benzyl Boc or BOCtert-butoxycarbonyl Bu butyl Bz benzoyl calc'd calculated cBu cyclobutylCbz benyzloxycarbonyl cHex cyclohexyl cPen cyclopentyl cPr cyclopropylDCE 1,2-dichloroethane DCM dichloromethane DIEA or Hünig's baseN,N-diisopropylethyl-amine DMA 1,2-dimethylacetamide DMFdimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide EDTA ethylenediamine tetraacetic acidESI electrospray ionization Et ethyl EtOH ethanol EtOAc ethyl acetate ggrams h hour HATU N,N,N′,N′-tetramethyl- O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HOBt 1-hydroxybenzotriazole HPLChigh-performance liquid chromatography IPA isopropanol iPr isopropyl LCliquid chromatography LCMS liquid chromatography mass spectrometry mCPBAm-choroperoxybenzoic acid Me methyl MeOH methanol mg milligrams minminute μL microliters mL milliliters mmol millimoles MS massspectrometry Ms methanesulfonyl (mesyl) MTBE methyl tert-butyl ether NMRnuclear magnetic resonance spectroscopy obsv'd observed Ph phenyl Prpropyl rac racemic mixture RT or rt room temperature (ambient, about 25°C.) sat or sat'd saturated SFC supercritical fluid chromatography tButert-butyl TEA triethylamine (Et₃N) TFA trifluoroacetic acid THFtetrahydrofuran TLC thin layer chromatography

Several methods for preparing the compounds of this invention aredescribed in the following Schemes and Examples. Starting materials andintermediates are purchased or are made using known procedures, or asotherwise illustrated. A frequently applied route to the compounds ofFormula I are described in the Scheme that follows. In some cases theorder of carrying out the reaction steps in the schemes may be varied tofacilitate the reaction or to avoid unwanted reaction products.

Symmetrical compounds of Formula II can be prepared from(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid,referred to herein as TFV, with variably-substituted beta-amino estersin a one-step one-pot condensation reaction with 2,2′-dipyridyldisulfide(Aldrithiol), triphenylphosphine, and base. Amino esters that are notcommercially available can be readily prepared by condensation betweenthe corresponding amino acid and alcohols with thionyl chloride.

Multiple procedures have been developed for the synthesis ofunsymmetrical compounds of the Formula IV and Formula V. In one suchexample, compounds of the Formula S-III can be prepared from TFV, withL-amino esters under EDC coupling conditions. The subsequent reaction ofS-III with a corresponding beta-amino ester under2,2′-dipyridyldisulfide (Aldrithiol) condensation conditions yields theproducts of the Formula S-V. Amino esters that are not commerciallyavailable can be readily prepared by condensation between thecorresponding amino acid and alcohols with thionyl chloride.

Similarly, compounds of the Formula R-III can be prepared from TFV, withD-amino esters under EDC coupling conditions. The subsequent reaction ofR-III with a corresponding beta-amino ester under2,2′-dipyridyldisulfide (Aldrithiol) condensation conditions yields theproducts of the Formula R-IV. Amino esters that are not commerciallyavailable can be readily prepared by condensation between thecorresponding amino acid and alcohols with thionyl chloride.

Finally, unsymmetrical compounds of the Formula V can be prepared in atwo-step one-pot procedure. In this caseTFV is initially condensed withgeminally di-substituted unnatural amino esters in the first step with2,2′-dipyridyldisulfide (Aldrithiol), triphenylphosphine, and base.Next, variably substituted beta-amino esters are added to the one-potreaction to furnish the products of the Formula V. Amino esters that arenot commercially available can be readily prepared by condensationbetween the corresponding amino acid and alcohols with thionyl chloride.

Reactions sensitive to moisture or air were performed under nitrogen orargon using anhydrous solvents and reagents. The progress of reactionswas determined by either analytical thin layer chromatography (TLC)usually performed with E. Merck pre-coated TLC plates, silica gel60F-254, layer thickness 0.25 mm or liquid chromatography-massspectrometry (LC-MS).

Typically the analytical LC-MS system used consisted of a Waters ZQ™platform with electrospray ionization in positive ion detection modewith an Agilent 1100 series HPLC with autosampler. The column wascommonly a Waters Xterra MS C18, 3.0×50 mm, 5 μm or a Waters AcquityUPLC® BEH C18 1.0×50 mm, 1.7 μm. The flow rate was 1 mL/min, and theinjection volume was 10 μL. UV detection was in the range 210-400 nm.The mobile phase consisted of solvent A (water plus 0.05% TFA) andsolvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solventA for 0.7 min changing to 100% solvent B over 3.75 min, maintained for1.1 min, then reverting to 100% solvent A over 0.2 min.

Preparative HPLC purifications were usually performed using either amass spectrometry directed system or a non-mass guided system. Usuallythey were performed on a Waters Chromatography Workstation configuredwith LC-MS System consisting of: Waters ZQ™ single quad MS system withElectrospray Ionization, Waters 2525 Gradient Pump, Waters 2767Injecto/Collector, Waters 996 PDA Detector, the MS Conditions of:150-750 amu, Positive Electrospray, Collection Triggered by MS, and aWaters SUNFIRE® C-18 5 micron, 30 mm (id)×100 mm column. The mobilephases consisted of mixtures of acetonitrile (10-100%/6) in watercontaining 0.1% TFA. Flow rates were maintained at 50 mL/min, theinjection volume was 1800 μL, and the UV detection range was 210-400 nm.An alternate preparative HPLC system used was a Gilson Workstationconsisting of: Gilson GX-281 Injector/Collector, Gilson UV/VIS-155Detector, Gilson 333 and 334 Pumps, and either a Phenomenex Gemini-NXC-18 5 micron, 50 mm (id)×250 mm column or a Waters XBridge™ C-18 5micron OBD™, 30 mm (id)×250 mm column. The mobile phases consisted ofmixtures of acetonitrile (0-75%) in water containing 5 mmol (NH₄)HCO₃.Flow rates were maintained at 50 mL/min for the Waters Xbridge™ columnand 90 mL/min for the Phenomenex Gemini column. The injection volumeranged from 1000-8000 μL, and the UV detection range was 210-400 nm.Mobile phase gradients were optimized for the individual compounds.Reactions performed using microwave irradiation were normally carriedout using an Emrys Optimizer manufactured by Personal Chemistry, or anInitiator manufactured by Biotage. Concentration of solutions wascarried out on a rotary evaporator under reduced pressure. Flashchromatography was usually performed using either a Biotage® FlashChromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus,or an ISCO CombiFlash® Companion XL on silica gel (32-63 μM, 60 Å poresize) in pre-packed cartridges of the size noted. ¹H NMR spectra wereacquired at 500 MHz spectrometers in CDCl₃ solutions unless otherwisenoted. Chemical shifts were reported in parts per million (ppm).Tetramethylsilane (TMS) was used as internal reference in CD₃Clsolutions, and residual CH₃OH peak or TMS was used as internal referencein CD₃OD solutions. Coupling constants (J) were reported in hertz (Hz).Chiral analytical chromatography was most commonly performed on one ofCHIRALPAK® AS, CHIRALPAK® AD, CHIRALCEL® OD, CHIRALCEL® IA, orCHIRALCEL® OJ columns (250×4.6 mm) (Daicel Chemical Industries, Ltd.)with noted percentage of either ethanol in hexane (% Et/Hex) orisopropanol in heptane (% IPA/Hep) as isocratic solvent systems. Chiralpreparative chromatography was conducted on one of CHIRALPAK AS, ofCHIRALPAK AD, CHIRALCEL® OD, CHIRALCEL® IA, CHIRALCEL® OJ columns(20×250 mm) (Daicel Chemical Industries, Ltd.) with desired isocraticsolvent systems identified on chiral analytical chromatography or bysupercritical fluid (SFC) conditions.

Unless specified otherwise, it is understood that each chiral center ina compound may exist in the “S” or “R” stereoconfiguration, or as amixture of both. Some compounds of Formula I may contain a phosphoruschiral center. Examples 6-28 contain a phosphorus chiral center. Theisomer mixture in each of Examples 6-28, was separated providing anIsomer #A, e.g., Isomer 6A (faster eluting isomer) and an Isomer #B,e.g., Isomer 6B (slower eluting isomer), based on their observed elutionorder resulting from the separation as performed in the Example.Retention times are provided only to show the relative order of elutionof each isomer in an Example. Elution order of separated isomers maydiffer if performed under conditions different than those employedherein. Absolute stereochemistry (R or S) of the phosphorus chiralcenter in each of the “A” and “B” separated stereoisomers in Examples6-23 and 26-28 was not determined and “A” and “B” only refer to elutionorder. Absolute stereochemistry (R or S) of the phosphorus chiral centerwas determined for each of the “A” and “B” separated isomers in Examples24 and 25. An asterisk (*) may be used in the associated chemicalstructure drawings of the Example compounds to indicate the phosphoruschiral center.

Intermediate A

(R)-isopropyl 3-aminobutanoate hydrochloride

Thionyl chloride (6.9 g, 58.2 mmol) was added dropwise to a solution of(R)-3-aminobutanoic acid (2 g, 19.4 mmol) in propan-2-ol (30 mL) at −50°C. The mixture was allowed to warm to ambient temperature, and thenheated at 80° C. for 6 hours. The reaction mixture was concentratedunder reduced pressure to give a residue, which was triturated withice-cold diethyl ether to provide the title compound: LC/MS:[(M+1)]⁺=146.1.

Intermediate B

(R)-cyclopentyl 2-aminopropanoate

INTERMEDIATE B was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (7.8 g,67.3 mmol) and (R)-2-aminopropanoic acid (2.0 g, 22.5 mmol) incyclopentanol (60 mL): LC/MS: [(M+1)]⁺=158.1.

Intermediate C

(S)-isopropyl 3-amino-2-methylpropanoate hydrochloride

INTERMEDIATE C was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (6.9 g,58.2 mmol) and (S)-3-aminobutanoic acid (2 g, 19.4 mmol) in propan-2-ol(30 mL): LC/MS: [(M+1)]⁺=146.2

Intermediate D

(R)-isopropyl 3-amino-2-methylpropanoate hydrochloride

INTERMEDIATE D was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (3.4 g,29.1 mmol) and (R)-3-amino-2-methylpropanoic acid (1 g, 9.7 mmol) inpropan-2-ol (30 mL): LC/MS: [(M+1)]⁺=146.1.

Intermediate E

(S)-isopropyl 3-amino-2-methylpropanoate hydrochloride

INTERMEDIATE E was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (3.4 g,29.1 mmol) and (S)-3-amino-2-methylpropanoic acid (1 g, 9.7 mmol) inpropan-2-ol (30 mL): LC/MS: [(M+1)]⁺=146.0.

Intermediate F

isopropyl (S)-3-amino-4-methylpentanoate hydrochloride

INTERMEDIATE F was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.16 g,68.6 mmol) and (S)-3-amino-4-methylpentanoic acid (3 g, 22.87 mmol) inpropan-2-ol (50 mL): LC/MS: [(M+1)]⁺=174.0.

Intermediate G

(S)-cyclopentyl 2-aminopropanoate

INTERMEDIATE G was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (7.8 g,67.3 mmol) and (S)-2-aminopropanoic acid (2.0 g, 22.5 mmol) incyclopentanol (60 mL): LC/MS: [(M+1)]⁺=158.0

Intermediate H

(S)-cyclobutyl 2-aminopropanoate hydrochloride

INTERMEDIATE H was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (7.8 g,67.3 mmol) and (S)-2-aminopropanoic acid (2.0 g, 22.5 mmol) incyclobutanol (30 mL): LC/MS: [(M+1)]⁺=144.2.

Intermediate I

(S)-cyclohexyl 2-aminopropanoate hydrochloride

INTERMEDIATE I was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (S)-2-aminopropanoic acid (2 g, 22.5 mmol) incyclohexanol (50 mL): LC/MS: [(M+1)]⁺=172.1.

Intermediate J

(S)-isobutyl 2-aminopropanoate hydrochloride

INTERMEDIATE J was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (S)-2-aminopropanoic acid (2 g, 22.5 mmol) in2-methylpropan-1-ol (50 mL): LC/MS: [(M+1)]⁺=146.2.

Intermediate K

(S)-butyl 2-aminopropanoate hydrochloride

INTERMEDIATE K was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (S)-2-aminopropanoic acid (2 g, 22.5 mmol) in butan-1-ol(50 mL): LC/MS: [(M+1)]⁺=146.2.

Intermediate L

(S)-pentyl 2-aminopropanoate hydrochloride

INTERMEDIATE L was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (S)-2-aminopropanoic acid (2 g, 22.5 mmol) in pentan-1-ol(50 mL): LC/MS: [(M+1)]⁺=160.2.

Intermediate M

(S)-heptyl 2-aminopropanoate hydrochloride

INTERMEDIATE M was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (S)-2-aminopropanoic acid (2 g, 22.5 mmol) in heptan-1-ol(50 mL): LC/MS: [(M+1)]⁺=188.2.

Intermediate N

(R)-cyclobutyl 2-aminopropanoate hydrochloride

INTERMEDIATE N was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (7.8 g,67.3 mmol) and (R)-2-aminopropanoic acid (2.0 g, 22.5 mmol) incyclobutanol (30 mL): LC/MS: [(M+1)]⁺=144.0.

Intermediate O

(R)-cyclohexyl 2-aminopropanoate hydrochloride

INTERMEDIATE O was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE A starting from thionyl chloride (8.0 g,67.3 mmol) and (R)-2-aminopropanoic acid (2 g, 22.5 mmol) incyclohexanol (50 mL): LC/MS: [(M+1)]⁺=172.1.

Intermediate P

isopropyl 2-amino-2-methylpropanoate hydrochloride

A neat solution of isopropanol (89 ml, 1164 mmol) was treated slowlywith thionyl chloride (15.57 ml, 213 mmol) at room temperature over a 2min period. (exotherm to ˜60° C.) The mixture was treated with2-amino-2-methylpropanoic acid (20 g, 194 mmol) and fitted with a refluxcondenser. This suspension was heated to 85° C. (reflux) and stirred for3 days. The resulting clear solution was concentrated to dryness. Theresulting oil was crystallized by tritutation in diethyl ether andhexanes. The solids were isolated by filtration and dried under highvacuum to provide the title compound: LC/MS: [(M+1)]⁺=146.1.

Intermediate Q

butyl 2-amino-2-methylpropanoate hydrochloride

INTERMEDIATE Q was prepared on 8 mmol scale in a similar fashion to thatdescribed for the synthesis of INTERMEDIATE P starting from2-amino-2-methylpropanoic acid, except using n-butanol to provide thetitle compound: LC/MS: [(M+1)]⁺=160.1.

Intermediate R

pentyl 2-amino-2-methylpropanoate hydrochloride

A neat solution of pentan-1-ol (205 g, 2327 mmol) was treated slowlywith thionyl chloride (15.57 ml, 213 mmol) at room temperature over a 10min period. The mixture was treated with 2-amino-2-methylpropanoic acid(40 g, 388 mmol) and fitted with a reflux condenser and stirred at 80°C. over the weekend. The reaction mixture was concentrated under reducedpressure and then dissolved in water (1 L) and washed with 1:1EtOAc/hexane (2×2 L), hexanes (1×2 L) and dichloromethane (3×1 L). Theaqueous layer was concentrated and azeotroped with acetonitrile and thentoluene. The residue was dried overnight under high vacuum. The solidswere triturated with ˜500 mL of diethyl ether, filtered and dried toafford the title compound: LC/MS: [(M+1)]⁺=174.2.

Intermediate S

hexyl 2-amino-2-methylpropanoate hydrochloride

INTERMEDIATE S was prepared on 388 mmol scale in a similar fashion tothat described for the synthesis of INTERMEDIATE R starting from2-amino-2-methylpropanoic acid, except using n-hexanol to provide thetitle compound: LC/MS: [(M+1)]⁺=187.9.

Intermediate T

isobutyl 2-amino-2-methylpropanoate hydrochloride

INTERMEDIATE T was prepared on 36.8 mmol scale in a similar fashion tothat described for the synthesis of INTERMEDIATE R starting from2-amino-2-methylpropanoic acid, except using isobutanol to provide thetitle compound: LC/MS: [(M+1)]⁺=160.1.

Intermediate U

P-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-N-[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]phosphonamidicacid

To a solution of(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid(referred to herein as TFV, 3.0 g, 10.5 mmol) in water (50 mL) wereadded EDC (10.0 g, 52.2 mmol) and (S)-isopropyl 2-aminopropanoatehydrochloride (8.8 g, 52.2 mmol) at ambient temperature. The pH value ofthe resulting solution was adjusted to 7.2-7.6 with TEA (5.3 g, 52.2mmol). The resulting mixture was stirred at 40° C. for 16 hours. Uponreaction completion, the reaction mixture was cooled down to ambienttemperature and concentrated under reduced pressure. The residue waspurified by flash chromatography under the following condition: Column:C18, 330 g, 20-35 μm, 100 Å; Mobile Phase A: Water with 5 mM NH₄HCO₃;Mobile Phase B: ACN; Gradient: 5-20% B in 25 min; Flow rate: 50 mL/min;Detector 254 nm; retention time: 18 min to afford the title compound:LC/MS: [(M+1)]⁺=401.2.

Intermediate V

P-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-N-[(1R)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]phosphonamidicacid

INTERMEDIATE V was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with (R)-isopropyl2-aminopropanoate hydrochloride: LC/MS: [(M+1)]⁺=401.2.

Intermediate W

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-isobutoxy-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE W was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE J:LC/MS: [(M+1)]⁺=415.0.

Intermediate X

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-3-isopropoxy-2-methyl-3-oxopropyl)phosphonamidicacid

INTERMEDIATE X was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE E:LC/MS: [(M+1)]⁺=415.1.

Intermediate Y

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-cyclobutoxy-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE Y was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE H:LC/MS: [(M+1)]⁺=413.0.

Intermediate Z

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-(cyclohexyloxy)-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE Z was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE I:LC/MS: [(M+1)]⁺=441.1.

Intermediate AA

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-butoxy-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE AA was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE K:LC/MS: [(M+1)]⁺=415.0

Intermediate BB

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-oxo-1-(pentyloxy)propan-2-yl)phosphonamidicacid

INTERMEDIATE BB was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE L:LC/MS: [(M+1)]⁺=457.2

Intermediate CC

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((S)-1-(heptyloxy)-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE CC was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE M:LC/MS: [(M+1)]⁺=429.0

Intermediate DD

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((R)-1-cyclobutoxy-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE DD was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE N:LC/MS: [(M+1)]⁺=412.9

Intermediate EE

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((R)-1-(cyclohexyloxy)-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE EE was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE O:LC/MS: [(M+1)]⁺=441.1

Intermediate FF

P—(((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)-N—((R)-1-(cyclopentyloxy)-1-oxopropan-2-yl)phosphonamidicacid

INTERMEDIATE FF was prepared in a similar fashion to that described forthe synthesis of INTERMEDIATE U starting from TFV with INTERMEDIATE B:LC/MS: [(M+1)]⁺=427.0

Intermediate HH

(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl phosphonicdichloride hydrochloride (HH)

To a stirred suspension of(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acidhydrochloride (30 g, 93 mmol) in acetonitrile (600 mL) was added thionylchloride (27.1 mL, 371 mmol) and the mixture was heated to 75° C. for 8h. The mixture was cooled to room temperature and attached to adistillation apparatus. The reaction mixture was then heated to 40° C.under vacuum to carry out distillation. Distillation continued until thevolume of the reaction mixture reached 150 mL. The resulting slurry wasstirred at room temperature overnight. The flask was transferred to aglove box and the solid was filtered. The solid was washed with 2-MeTHF(100 mL). The solid was then dried under vacuum in the glove box toprovide INTERMEDIATE HH as a solid.

For characterization by ³¹P NMR, INTERMEDIATE HH was dissolved inanhydrous MeOH to prepare the bis-methoxy adduct of HH: ³¹P NMR (202.5MHz; CD₃OD) δ 24.55; LCMS: [(M+1)]⁺=316.11.

Example 1

1-methylethyl8-{[(R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2-methyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate8-oxide (1) Step 1: Isopropyl 3-aminopropanoate hydrochloride(INTERMEDIATE GG)

Thionyl chloride (2.0 g, 16.8 mmol) was added dropwise to a solution of3-aminopropanoic acid (0.5 g, 5.61 mmol) in propan-2-ol (10 mL) at −50°C. The mixture was allowed to warm to ambient temperature, and thenheated at 80° C. for 6 h. The reaction mixture was concentrated underreduced pressure to provide a residue, which was triturated withice-cold diethyl ether to provide the title compound: LC/MS:[(M+1)]⁺=132.1.

Step 2: 1-methylethyl8-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2-methyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate8-oxide

To a suspension of(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid(referred to herein as TFV, 100 mg, 0.35 mmol) in pyridine (5 mL) wereadded INTERMEDIATE GG (183 mg, 1.39 mmol), Et₃N (211 mg, 2.09 mmol),PPh₃ (365 mg, 1.39 mmol) and 1,2-di(pyridin-2-yl)disulfane (Aldrithiol,307 mg, 1.39 mmol) at ambient temperature. The resulting mixture wasstirred at 60° C. for 16 hours under a N₂ atmosphere. The mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was purified by gradient elution on silica gel (1% to 10%MeOH/CH₂Cl₂) to afford the title compound: ¹H NMR (400 MHz; CDCl₃) δ8.37 (s, 1H), 8.03 (s, 1H), 6.04 (br s, 2H), 5.07-4.99 (m, 2H), 4.40(dd, J=3.2; 14.4 Hz, 1H), 4.15 (dd, J=7.6; 14.4 Hz, 1H), 3.94-3.90 (m,1H), 3.77 (dd, J=8.4; 12.8 Hz, 1H), 3.46 (dd, J=8.4; 12.8 Hz, 1H),3.25-3.09 (m, 6H), 2.49 (t, J=6.4 Hz, 2H), 2.44 (t, J=6.4 Hz, 2H),1.26-1.23 (m, 15H); ³¹P NMR (162 MHz; CDCl₃) δ 23.12; LC/MS:[(M+1)]⁺=514.1.

1A: Alternate Method to Prepare Compound 1

A mixture of INTERMEDIATE HH (200 mg, 0.62 mmol) and INTERMEDIATE GG(217 mg, 1.30 mmol) in 2-MeTHF (1.65 mL)/DCM (0.41 mL) was treated withtrimethylamine (0.43 mL, 3.1 mmol) and stirred at room temperature for 2h. The mixture was concentrated and the residue was dissolved in 1:1MeCN/water (4 mL) and purified directly by reverse phase chromatography(XBridge 10 μm C18 30×250 mm column; 10-70% CH₃CN in a 5 mM solution ofNH₄HCO₃ over 30 min) to afford compound 1: LC/MS: [(M+1)]⁺=514.1.

The compounds in Table 1 were prepared in an analogous fashion to thatdescribed for Example 1. The column having the heading INT provides theintermediate example compound used to make each exemplified compound.

TABLE 1 LC/MS Ex. Structure IUPAC Name (M + 1)⁺ INT. 2

1-methylethyl (6R,10R)-8-{[(1R)- 2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2,6,10- trimethyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate 8- oxide Calc'd 542.3, found 542.1 A 3

1-methylethyl (5S,11S)-8-{[(1R)- 2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2,5,11- trimethyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate 8- oxide Calc'd 542.3, found 542.2 E 4

1-methylethyl (5R,11R)-8-{[(1R)- 2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2,5,11- trimethyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate 8- oxide Calc'd 542.3, found 542.1 D 5

1-methylethyl (6S,10S)-8-{[(1R)- 2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-2,6,10- trimethyl-4-oxo-3-oxa-7,9-diaza-8-phosphadodecan-12-oate 8- oxide Calc'd 542.3, found 542.5 C Ex. ³¹PNMR shift (ppm) Purification conditions 2 20.20 (162 MHz; CDCl₃) silicagel column chromatography, eluted with DCM:MeOH (50:1 to 10:1) 3 23.13(162 MHz; CDCl₃) silica gel column chromatography, eluted with DCM:MeOH(50:1 to 10:1) 4 23.01 (162 MHz, CDCl₃) silica gel columnchromatogrpahy, eluted with DCM:MeOH (50:1 to 10:1) 5 23.01 (162 MHz,CD₃OD) silica gel column chromatography, eluted with DCM:MeOH (50:1 to10:1)

Examples 6A and 6B

1-methylethylN—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate,and 1-methylethylN—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate(6A and 6B)

To a solution of INTERMEDIATE U (100 mg, 0.25 mmol) in pyridine (5 mL)were added INTERMEDIATE E (43.5 mg, 0.30 mmol), Et₃N (50 mg, 0.50 mmol),1,2-di(pyridin-2-yl)disulfane (Aldrithiol, 110 mg, 0.50 mmol) and PPh₃(131 mg, 0.50 mmol) at ambient temperature. The resulting mixture wasstirred at 60° C. for 3 hours under a N₂ atmosphere. The reactionmixture was cooled to ambient temperature and concentrated under reducedpressure. The residue was purified by gradient elution on silica gelcolumn (1% to 10% MeOH/CH₂Cl₂) to afford a mixture of two isomers atphosphorous. These isomers were then separated by preparativeChiral-HPLC under the following conditions: Column: Chiralpak IA 2×25cm, 5 um; Mobile Phase: Hexane/EtOH (80/20, 25 min); Flow rate: 20mL/min; Detector 254/220 nm to afford Isomer 6A (faster eluting, RT=14.2min) as a solid: ¹H NMR (400 MHz; CD₃OD) δ 8.24 (s, 1H), 8.22 (s, 1H),5.04-4.97 (m, 2H), 4.39 (dd, J=3.2 Hz, 14.4 Hz, 1H), 4.25 (q, J=7.2 Hz,1H), 3.97-3.94 (m, 1H), 3.90-3.85 (m, 1H), 3.80 (dd, J=8.8; 13.2 Hz,1H), 3.55 (dd, J=9.6; 13.2 Hz, 1H), 3.03-2.98 (m, 1H), 2.88-2.82 (m,1H), 2.54-2.50 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.31-1.22 (m, 15H), 1.09(d, J=6.8 Hz, 3H); ³¹P NMR (162 MHz; CD₃OD) δ 24.87; LC/MS:[(M+1)]⁺=528.5; and Isomer 6B (slower eluting, RT=20 min) as a solid: ¹HNMR (400 MHz; CD₃OD) δ 8.23 (s, 2H), 5.05-4.99 (m, 1H), 4.95-4.90 (m,1H), 4.42 (dd, J=3.2; 14.4 Hz, 1H), 4.24 (q, J=7.2 Hz, 1H), 3.99-3.97(m, 1H), 3.85-3.79 (m, 2H), 3.57 (dd, J=10.8; 13.2 Hz, 1H), 3.16-3.09(m, 1H), 2.98-2.91 (m, 1H), 2.59-2.51 (m, 1H), 1.33 (d, J=7.2 Hz, 3H),1.26-1.21 (m, 15H), 1.15 (d, J=6.8 Hz, 3H); ³¹P NMR (162 MHz; CD₃OD) δ25.04; LC/MS: [(M+1)]⁺=528.4.

Example 7A and 7B

1-methylethylN—[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninateand 1-methylethylN—[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate(7A and 7B)

The two title compounds were prepared in the same fashion as describedfor example 6A/B from INTERMEDIATE U and INTERMEDIATE AA. The twoisomers were separated by Prep-HPLC under the following conditions:Column: X Bridge C18, 19×150 mm, 5 μm; Mobile Phase A (10 mmol/L NH₄HCO₃in water), Mobile Phase B (CH₃CN); Gradient: 25-30% B in 10 min. Flowrate: 20 mL/min; Detector: 254/220 nm; to afford Isomer 7A (fastereluting, RT=5.5 min) as a solid: ¹H NMR (400 MHz; CD₃OD) δ 8.23 (s, 1H),8.22 (s, 1H), 5.03-4.95 (m, 2H), 4.40 (dd, J=3.2; 14.4 Hz, 1H), 4.28(dd, J=7.2; 14.4 Hz, 1H), 3.98-3.95 (m, 1H), 3.88 (d, J=8.8 Hz, 1H),3.79 (dd, J=7.6; 13.2 Hz, 1H), 3.56 (dd, J=9.6; 13.2 Hz, 1H), 3.10-3.05(m, 2H), 2.43 (t, J=6.8 Hz, 2H), 1.35 (d, J=7.2 Hz, 3H), 1.28-1.21 (m,15H); ³¹P NMR (162 MHz; CD₃OD) δ 24.93 (decoupled); LC/MS:[(M+1)]⁺=514.5; and Isomer 7B (slower eluting, RT=7.3 min) as a solid:¹H NMR (400 MHz; CD₃OD) δ 8.23 (s, 1H), 8.22 (s, 1H), 5.03 (q, J=6.0 Hz,1H), 4.90 (q, J=6.0 Hz, 1H), 4.43 (dd, J=3.2; 14.4 Hz, 1H), 4.25 (dd,J=7.2; 14.8 Hz, 1H), 3.98-3.95 (m, 1H), 3.83-3.77 (m, 2H), 3.58 (dd,J=10.4; 12.8 Hz, 1H), 3.18-3.12 (m, 2H), 2.47 (t, J=6.8 Hz, 2H), 1.33(d, J=7.2 Hz, 3H), 1.27-1.21 (m, 15H); ³¹P NMR (162 MHz; CD₃OD) δ 25.16(decoupled); LC/MS: [(M+1)]⁺=514.5.

The compounds in Table 2 were prepared in an analogous fashion to thatdescribed for Example 6A/B. The column having the heading INT providesthe intermediate example compounds used to make each exemplifiedcompound. The diastereoisomers were separated by either Prep-HPLC orpreparative Chiral-HPLC. Absolute stereochemistry of the “A” isomer(faster eluting) and “B” isomer (slower eluting) of each example was notdetermined.

TABLE 2 LC/MS Ex. EXAMPLE STRUCTURE/NAME (M + 1)⁺ INT.  8A and  8B

528.5 and 528.5 C and O 1-methylethyl(3S)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate; and 1-methylethyl(3S)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate  9A and  9B

528.5 and 528.5 A and O 1-methylethyl(3R)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate; and 1-methylethyl(3R)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1S)-1-methyl-2-(1-methylethoxy)-2-oxoethyl]amino}phosphoryl]amino}butanoate 10A and 10B

528.4 and 528.5 D and O 1-methylethylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2R)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and 1-methylethylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2R)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 11A and 11B

554.4 and 554.4 E and G cyclopentylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and cyclopentylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 12A and 12B

540.2 and 540.2 E and Y cyclobutylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and cyclobutylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 13A and 13B

568.5 and 568.5 E and Z cyclohexylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and cyclohexylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 14A and 14B

542.5 and 542.4 E and W 2-methylpropylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and 2-methylpropylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 15A and 15B

542.4 and 542.3 E and AA butylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and butylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 16A and 16B

556.5 and 556.5 E and BB pentylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and pentylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate 17A and 17B

584.3 and 584.3 E and CC heptylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate; and heptylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-L-alaninate Retention Ex. ³¹P NMR shift(ppm) Purification conditions time (min)  8A 23.25 (162 MHz; Column:Chiralpak IA 2 * 25 cm, 5 um; 13.5 CD₃OD) Mobile Phase A: Hexane; MobilePhase  8B 23.51 (162 MHz; B: EtOH; Flow rate: 18 mL/min; 23.0 CD₃OD)Gradient: 20% B in 30 min; Detector 254 nm  9A 23.57 (162 MHz; Column:XBridge Prep C18 OBD, 1.9 * 7.5 CD₃OD) 15 cm, 5 um; Mobile Phase A:Water  9B 23.20 (162 MHz; (plus 10 mM NH₄HCO₃); Mobile Phase 8.7 CD₃OD)B: ACN; Flow rate: 20 mL/min; Gradient: 25% to 31% B in 11 min; Detector254 nm 10A 25.19 (162 MHz; Column: Chiralpak AD-H 2.1 * 15 cm, 5 15.0CD₃OD) um; Mobile Phase A: Hexane; Mobile 10B 24.80 (162 MHz; Phase B:EtOH; Flow rate: 20 mL/min; 22.5 CD₃OD) Gradient: 20% B in 30 min;Detector: 254 nm 11A 24.87 (162 MHz; Column: Chiralpak IA 2 * 25 cm, 5um; 11.3 CD₃OD) Mobile Phase A: Hexane (plus 0.1% IPA, 11B 25.05 (162MHz; v/v); Mobile Phase B: EtOH; Flow rate: 18.6 CD₃OD) 20 mL/min;Gradient: 30% B in 25 min; Detector: 254 nm 12A 24.89 (162 MHz; Column:Chiralpak IA 2 * 25 cm, 5 um; 23.0 CD₃OD) Mobile Phase A: Hexane, MobilePhase 12B 25.04 (162 MHz; B: EtOH; Flow rate: 20 mL/min; 38.0 CD₃OD)Gradient: 15% B in 45 min; Detector: 254 nm 13A 24.88 (162 MHz; Column:Chiralpak IA 2 * 25 cm, 5 um; 9.3 CD₃OD) Mobile Phase A: Hexane (plus0.1% 13B 25.08 (162 MHz; DEA, v/v); Mobile Phase B: EtOH; Flow 16.4CD₃OD) rate: 20 mL/min; Gradient: 30% B in 30 min; Detector: 254 nm 14A24.87 (162 MHz; Column: Chiralpak IA 2 * 25 cm, 5 um; 14.0 CD₃OD) MobilePhase A: Hexane (plus 0.1% 14B 25.05 (162 MHz; DEA, v/v); Mobile PhaseB: EtOH; Flow 20.6 CD₃OD) rate: 20 mL/min; Gradient: 20% B in 30 min;Detector: 254 nm 15A 24.88 (162 MHz; Column: Chiralpak IA 2 * 25 cm, 5um; 14.0 CD₃OD) Mobile Phase A: Hexane (plus 0.1% 15B 25.05 (162 MHz;DEA, v/v); Mobile Phase B: EtOH; 21.0 CD₃OD) Flow rate: 20 mL/min;Gradient: 20% B in 26 min; Detector: 254 nm 16A 24.87 (162 MHz; Column:Chiralpak IA 2 * 25 cm, 5 um; 11.0 CD₃OD) Mobile Phase A: Hexane (plus0.1% 16B 25.04 (162 MHz; DEA, v/v); Mobile Phase B: EtOH; 15.4 CD₃OD)Flow rate: 20 mL/min; Gradient: 25% B in 18 min; Detector: 254 nm 17A25.04 (162 MHz; Column: chiral pak AS-H 2 * 25 cm, 5 7.9 CD₃OD) um;Mobile Phase A: Hexane (plus 0.2% 17B 24.88 (162 MHz; IPA, v/v), MobilePhase B: EtOH; Flow 11.5 CD₃OD) rate: 20 mL/min; Gradient: 80% to 20% Bin 16.5 min; Detector: 254 nm

Example 18A and 18B

isopropyl(3R)-3-(((S)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)butanoate;and isopropyl(3R)-3-(((R)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(((R)-1-cyclobutoxy-1-oxopropan-2-yl)amino)phosphoryl)amino)butanoate(18A and 18B)

The two title compounds were prepared in the same way as described forexample 6A/B from INTERMEDIATE DD and INTERMEDIATE A, and purified bypreparative Chiral HPLC with the following condition: Column: ChiralpakIA 2×25 cm, 5 um; Mobile Phase: Hexane/EtOH (85/15) in 30 min; Flowrate: 20 mL/min; Detector: 254/220 nm to afford Isomer 18A (fastereluting, RT=18.7 min) as a solid: ¹H NMR (300 MHz; CD₃OD) δ 8.18 (s,1H), 8.16 (s, 1H), 4.97-4.91 (m, 2H), 4.34 (dd, J=3.3; 14.4 Hz, 1H),4.23 (dd, J=6.9; 21.3 Hz, 1H), 3.95-3.91 (m, 1H), 3.91-3.82 (m, 1H),3.79-3.72 (m, 1H), 3.65-3.58 (m, 1H), 3.53-3.48 (m, 1H), 2.43-2.25 (m,4H), 2.12-1.97 (m, 2H), 1.81-1.75 (m, 1H), 1.63-1.57 (m, 1H), 1.35 (d,J=7.2 Hz, 3H), 1.20-1.15 (m, 9H), 1.04 (d, J=6.6 Hz, 3H); ³¹P NMR (121MHz, CD₃OD) δ 23.37; LC/MS: [(M+1)]⁺=540.1; and Isomer 18B (slowereluting, RT=25.3 min) as a solid: ¹H NMR (300 MHz; CD₃OD) δ 8.18 (s,1H), 8.17 (s, 1H), 4.97-4.91 (m, 2H), 4.34 (dd, J=3.3; 14.4 Hz, 1H),4.19 (dd, J=6.9; 21.3 Hz, 1H), 3.93-3.89 (m, 1H), 3.81-3.69 (m, 2H),3.65-3.48 (m, 2H), 2.47 (dd, J=5.7; 17.4 Hz, 1H), 2.34-2.27 (m, 3H),2.11-1.98 (m, 2H), 1.81-1.75 (m, 1H), 1.69-1.59 (m, 1H), 1.25 (d, J=7.2Hz, 3H), 1.19-1.13 (m, 12H); ³¹P NMR (121 MHz; CD₃OD) δ 23.289; LC/MS:[(M+1)]⁺=540.1

The compounds in Table 3 were prepared in an analogous fashion to thatdescribed for Example 18A and 18B. The column having the heading INTprovides the intermediate example compounds used to make eachexemplified compound. The diastereoisomers were separated by one of thefour listed methods: reverse phase HPLC, chiral HPLC, SFC, or prep TLC.Absolute stereochemistry of the “A” isomer (faster eluting) and “B”isomer (slower eluting) of each example was not determined.

TABLE 3 LC/MS Ex. EXAMPLE STRUCTURE/NAME (M + 1)⁺ INT. 19A and 19B

540.1 and 540.1 C and DD 1-methylethyl(3S)-3-{[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1R)-2-(cyclobutyloxy)-1-methyl-2-oxoethyl]amino}phosphoryl]amino}butanoate; and 1-methylethyl(3S)-3-{[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(1R)-2-(cyclobutyloxy)-1-methyl-2-oxoethyl]amino}phosphoryl]amino}butanoate 20A and 20B

540.2 and 540.2 E and DD cyclobutylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate; and cyclobutylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate 21A and 21B

568.5 and 568.5 E and EE cyclohexylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate; and cyclohexylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate 22A and 22B

554.4 and 554.4 E and FF cyclopentylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate; and cyclopentylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[(2S)-2-methyl-3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate 23A and 23B

526.5 and 526.5 GG and DD cyclobutylN-[(S)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate; and cyclobutylN-[(R)-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}{[3-(1-methylethoxy)-3-oxopropyl]amino}phosphoryl]-D-alaninate Retention Ex. ³¹P NMR shift(ppm) Purification conditions time (min) 19A 23.40 (162 MHz; CD₃OD)Column: X Bridge C18, 1.9 * 15 cm, 5 8.6 um; Mobile Phase A: Water (plus10 mM) 19B 23.24 (162 MHz; CD₃OD) NH₄HCO₃) Mobile Phase B: ACN; Flow10.2 rate: 20 mL/min; Gradient: 10% to 90% B in 15 min; Detector: 254 nm20A 24.83 (162 MHz; CD₃OD) Column: Chiralpak AD-H 2 * 25 cm; 13.0 MobilePhase A: Hexane (plus 0.2% IPA, 20B 25.02 (162 MHz; CD₃OD) v/v), MobilePhase B: EtOH; Flow rate: 21.0 20 mL/min; Gradient: 20% B in 25 min;Detector: 254 nm 21A 24.82 (162 MHz; CD₃OD) Column: Chiralpak IA 2 * 25cm, 5 um; 13.0 Mobile Phase A: Hexane (plus 0.2% IPA, 21B 25.03 (162MHz; CD₃OD) v/v); Mobile Phase B: i-PrOH; Flow rate: 20.0 20 mL/min;Gradient: 20% B in 30 min; Detector: 254 nm 22A 24.82 (162 MHz; CD₃OD)Column: Chiralpak AD-H 2 * 25 cm, 5 10.6 um; Mobile Phase A: Hexane(plus 0.2% 22B 25.04 (162 MHz; CD₃OD) DEA, v/v); Mobile Phase B: EtOH;Flow 14.7 rate: 20 mL/min; Gradient: 30% B in 16 min; Detector: 254 nm23A 24.92 (162 MHz; CD₃OD) Column: Chiralpak AD-H 2 * 25 cm, 5 22.3 um;Mobile Phase A: Hexane (plus 0.2% 23B 25.08 (162 MHz; CD₃OD) DEA, v/v);Mobile Phase B: EtOH; Flow 29.2 rate: 20 mL/min; Gradient: 20% B in 35min; Detector: 254 nm

Example 24A and 24B

isopropyl(3S)-3-(((S)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate(24A); and isopropyl(3S)-3-(((R)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate(24B)

To a mixture of TFV (5.0 g, 17.4 mmol), INTERMEDIATE R (5.5 g, 26.1mmol) and Et₃N (14.1 g, 139 mmol) in pyridine (500 mL) were added PPh₃(18.3 g, 69.6 mmol) and 2,2′-dipyridylsulfide (Aldrithiol, 15.3 g, 69.6mmol). The resulting mixture was stirred for 3 hours at 60° C. under aN₂ atmosphere followed by the addition of INTERMEDIATE F (3.6 g, 17.4mmol). After stirring for an additional 16 hours at 60° C., theresulting mixture was concentrated under reduced pressure and theresidue was dissolved into EtOAc (500 mL), washed with saturated aqueousammonium chloride (3×100 mL) and brine (100 mL), and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by gradient elution onsilica gel (1% to 10% methanol/CH₂Cl₂) to remove most of the impurities.The residue was further purified by Prep-HPLC under the followingconditions: Column: X Bridge C18, 330 g, 20-35 μm, 100 Å; Mobile Phase A(5 mM NH₄HCO₃ in water), Mobile Phase B (CH₃CN); Gradient: 10 to 25% Bover 15 min; then 25% to 45% B over 20 min; then 45% to 55% B over 10min; then isocratic at 95% B for 8 min; Flow rate: 70 mL/min; Detector:254 nm; Rt: 38 min to give provide an inseparable mixture of the titlecompounds. The two isomers were separated by Prep-SFC with the followingcondition: Column: CHIRALPAK IA, 5 cm*25 cm; Mobile Phase A: CO₂ (65%),Mobile Phase B: IPA with 0.2% isopropylamine (35%); Flow rate: 160mL/min; Detector: 220 nm; to afford the faster eluting Isomer 24A(Rt-4.83 min): ¹H NMR (400 MHz; CD₃OD) δ 8.22 (s, 1H), 8.21 (s, 1H),4.98-4.95 (m, 1H), 4.35 (dd, J=14.0, 2.8 Hz, 1H), 4.23 (dd, J=14.0, 6.8Hz, 1H), 4.13-4.09 (m, 2H), 3.98-3.91 (m, 1H), 3.71 (dd, J=12.8, 8.4 Hz,1H), 3.52-3.45 (m, 1H), 3.24-3.19 (m, 1H), 2.48-2.35 (m, 2H), 1.78-1.65(m, 4H), 1.52-1.49 (m, 6H), 1.38-1.32 (m, 4H), 1.22-1.19 (m, 8H), 1.02(t, J=7.6 Hz, 2H), 0.92 (t, J=6.8 Hz, 3H), 0.81-0.79 (m, 4H); ³¹P NMR(162 MHz; CD₃OD) S 21.33; LC/MS: [(M+1)]⁺=598.4; and the slower elutingIsomer 24B (Rt=5.60 min): ¹H NMR (400 MHz; CD₃OD) δ 8.23 (s, 1H), 8.21(s, 1H), 4.97-4.94 (m, 1H), 4.40 (dd, J=14.0, 2.8 Hz, 1H), 4.23 (dd,J=14.0, 6.8 Hz, 1H), 4.13-4.09 (m, 2H), 4.01-3.91 (m, 1H), 3.78 (dd,J=12.8, 8.4 Hz, 1H), 3.52 (dd, J=12.8, 10.0 Hz, 1H), 3.38-3.35 (m, 1H),2.45 (dd, J=6.4, 1.6 Hz, 2H), 1.78-1.72 (m, 1H), 1.71-1.62 (m, 2H), 1.47(s, 3H), 1.43 (s, 3H), 1.37-1.32 (m, 4H), 1.23-1.18 (m, 9H), 0.93-0.88(m, 9H); ³¹P NMR (162 MHz; CD₃OD) δ 22.53; LC/MS: [(M+1)]⁺=598.4.

Example 25A and 25B

isopropyl(3S)-3-(((S)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl((1-isopropoxy-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate(25A); and isopropyl(3S)-3-(((R)—((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-isopropoxy-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate(25B)

To a suspension of(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid(5.0 g, 17.4 mmol) in pyridine (500 mL) were added INTERMEDIATE P (3.8g, 20.9 mmol), Et₃N (14.1 g, 139.6 mmol), triphenylphosphine (18.3 g,69.8 mmol) and 2,2′-dipyridylsulfide (Aldrithiol, 15.3 g, 69.8 mmol).The resulting mixture was stirred for 3 hours at 60° C. under nitrogenatmosphere followed by the addition of INTERMEDIATE F (4.1 g, 19.2mmol). After stirring for additional 16 hours at 60° C., the resultingmixture was concentrated under reduced pressure and the residue wasdissolved into ethyl acetate (500 mL), washed with saturated aqueoussolution of ammonium chloride (3×100 mL), brine (100 mL) and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure and the residue was purified by gradient elution onsilica gel (1% to 10% methanol/CH₂Cl₂) to afford the title compound as amixture of diastereomers. The two diastereomers were separated byPrep-SFC with the following condition: Column: CHIRALPAK AD-H 5*25 cm, 5um; Mobile Phase A: CO₂: 60%, Mobile Phase B: IPA (0.2% DEA): 40%; Flowrate: 160 mL/min; Detector: UV 254 nm; to afford the faster elutingIsomer 25A (Rt=3.27 min): ¹H NMR (300 MHz, CD₃OD) δ 8.24 (s, 1H), 8.23(s, 1H), 5.05-4.97 (m, 2H), 4.38 (dd, J=14.4, 3.3 Hz, 1H), 4.23 (dd,J=14.4, 6.9 Hz, 1H), 4.03-3.97 (m, 1H), 3.81-3.77 (m, 1H), 3.56-3.49 (m,2H), 2.51-2.39 (m, 2H), 1.73-1.69 (m, 1H), 1.53 (s, 3H), 1.50 (s, 3H),1.28-1.14 (m, 15H), 0.93 (s, 3H), 0.92 (s, 3H); ³¹P NMR (162 MHz, CD₃OD)δ 21.29; LC/MS: [(M+1)]⁺=570.4; and the slower eluting Isomer 25B(Rt=5.41 min): ¹H NMR (300 MHz, CD₃OD) δ 8.20 (s, 1H), 8.18 (s, 1H),4.97-4.92 (m, 2H), 4.38 (dd, J=14.7, 3.3 Hz, 1H), 4.20 (dd, J=14.4, 7.2Hz, 1H), 3.97-3.92 (m, 1H), 3.78 (dd, J=12.9, 8.4 Hz, 1H), 3.50 (dd,J=12.9, 8.4 Hz, 1H), 3.38-3.32 (m, 1H), 2.42 (d, J=6.3 Hz, 2H),1.77-1.71 (m, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.23-1.17 (m, 15H),0.88-0.85 (m, 6H); ³¹P NMR (162 MHz, CD₃OD) δ 22.44; LC/MS:[(M+1)]⁺=570.4.

The compounds in Table 4 were prepared in an analogous fashion to thatdescribed for Example 24A and 24B. The column having the heading INTprovides the intermediate example compounds used to make eachexemplified compound. The diastereoisomers were separated by one of thefour listed methods: reverse phase HPLC, chiral HPLC, SFC, or prep TLC.Absolute stereochemistry of the “A” isomer (faster eluting) and “B”isomer (slower eluting) of each example was not determined.

TABLE 4 LC/MS Ex. EXAMPLE STRUCTURE/NAME (M + 1)⁺ INT. 26A and 26B

570.3 and 570.3 C and R isopropyl(3S)-3-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-butanoate; and isopropyl(3S)-3-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-ethyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-butanoate 27A and 27B

570.3 and 570.3 A and R isopropyl(3R)-3-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-butanoate; and isopropyl(3R)-3-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((2-methyl-1-oxo-1-(pentyloxy)propan-2-yl)amino)phosphoryl)amino)-butanoate 28A and 28B

612.4 and 612.4 F and S isopropyl(3S)-3-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate; and isopropyl(3S)-3-(((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)((1-(hexyloxy)-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)amino)-4-methylpentanoate Retention Ex. ³¹P NMRshift (ppm) Purification conditions time (min) 26A 22.19 (162 MHz;CD₃OD) Column: Gemini-NX Prep C18, 5 * 25 cm, 23.9 5 μm; Mobile Phase A:Water (plus 5 mM) 26B 21.81 (162 MHz; CD₃OD) NH₄HCO₃); Mobile Phase B:ACN; Flow 24.2 rate: 90 mL/min; Gradient: 20% to 60% B in 30 min;Detector: 254 nm 27A 18.85 (162 MHz; CDCl₃) Column: Gemini-NX Prep C18,5 * 25 cm, 23.9 5 μm; Mobile Phase A: Water (plus 5 mM) 27B 18.76 (162MHz; CDCl₃) NH₄HCO₃); Mobile Phase B: ACN; Flow 24.9 rate: 90 mL/min;Gradient: 20% to 60% B in 30 min; Detector: 254 nm 28A 22.53 (162 MHz;CD₃OD) Column: XBridge Prep C18 OBD, 1.9 * 25 19.35 cm, 10 um; MobilePhase A: Water (plus 28B 21.33 (162 MHz; CD₃OD) 10 mM NH₄HCO₃); MobilePhase B: 19.9 ACN; Flow rate: 20 mL/min; Gradient: 35% to 53% B in 24min; Detector: 254 nm

Example 29 Assessing Antiviral Potency in a Multiple Round HIV-1Infection Assay (Viking Assay)

The antiviral activity of the tenofovir prodrugs of the Examples hereinwas assessed in an assay that measures the rate of replication of HIV incell culture, termed the Viking assay (VIral KINetics in Green cells)and performed as follows. HIV-1 replication was monitored usingMT4-gag-GFP clone D3 (hereafter designated MT4-GFP), which are MT-4cells modified to harbor a GFP reporter gene, the expression of which isdependent on the HIV-1 expressed proteins tat and rev. Productiveinfection of an MT4-GFP cell with HIV-1 results in GFP expressionapproximately 24 h post-infection. MT4-GFP cells were maintained at 37°C./5% CO2/90% relative humidity in RPMI 1640 supplemented with 10% fetalbovine serum, 100 U/ml penicillin/streptomycin, and 400 μg/ml G418 tomaintain the reporter gene. For infections, MT4-GFP cells were placed inthe same medium lacking G418 and infected overnight with HIV-1 (H9/IIIBstrain) virus at an approximate multiplicity of infection of 0.01 in thesame incubation conditions. Cells were then washed and re-suspended ineither RPMI 1640 supplemented with 10% or 50% normal human serum (NHS)at 1.6×10⁵ cells/mL (10% NHS or 500% NHS, respectively). Compound plateswere prepared by dispensing compounds dissolved in DMSO into wells of384 well poly-D-lysine-coated plates (0.2 μl/well) using an ECHOacoustic dispenser. Each compound was tested in a 10-point serial 3-folddilution (typical final concentrations: 8.4 μM-0.42 nM). Controlsincluded no inhibitor (DMSO only) and a combination of three antiviralagents (efavirenz, indinavir, an in-house integrase strand transferinhibitor at final concentrations of 4 μM each). Cells were added (50μL/well) to compound plates and the infected cells were maintained at37° C./5% CO2/90% relative humidity.

Infected cells were quantified at two time points, ˜48 h and ˜72 hpost-infection, by counting the number of green cells in each well usingan Acumen eX3 scanner. The increase in the number of green cells over˜24 h period gives the reproductive ratio, R₀, which is typically 5-15and has been shown experimentally to be in logarithmic phase (data notshown). Inhibition of R₀ is calculated for each well, and IC₅₀sdetermined by non-linear 4-parameter curve fitting. Assay IC₅₀ resultsare shown in Table 5.

Example 30 Prodrug Stability Assay in Bio-Relevant Media

The following assay was employed to evaluate the stability of theprodrugs in simulated gastrointestinal tract conditions. Preparation offasted state simulated intestinal fluid (FaSSIF) using Phares SIF Powderwas carried out according to protocols from Phare Drug Delivery AG(Baselland, Switzerland). For sample preparation, 10 μL stock solutions(10 mM) of prodrug substance in DMSO was added to 990 μL of 0.5 mg/mLPancreatin solution (Fisher CAS#8049-47-6) in FaSSIF. Two samples wereprepared for each compound at initial. If the sample was clear solutionat the beginning, ran one sample directly as initial by HPLC; if thesample was not clear at starting, diluted the sample by 100% ACN. Putthe other sample under 37° C. and observed the sample at 5 h time-point.At 5 h time point, if the sample was clear solution then performed HPLCanalysis directly; if it was not clear solution, diluted the sample by100% ACN and assayed by HPLC. All the samples were vortexed for 3 minand observed before injection. For the diluted samples, the area will bemultiplied by a factor when data analysis. The analysis was carried outwith an Agilent 1100 series HPLC with autosampler. The column wasusually a Poroshell 120 EC-C18, 4.6×50 mm, 2.7 μm. The flow rate was 1.8mL/min, and the injection volume was 5 or 10 μL. UV detection was in therange 210-400 nm. The mobile phase consisted of solvent A (water plus 10mM tetrabutylammonium bromide) and solvent B (acetonitrile) with agradient of 90% solvent A at 0 min changing to 95% solvent B over 6 min,maintained for 1.5 min, then reverting to 90% solvent A over 1.6 min.The area of the parent in prodrug at 5 h time point was divided by thearea of the parent in prodrug at 0 h time point, to generate the %claimed parent ratio, which are summarized in Table 5 for GI Tractstability.

Example 31 Pharmacokinetic Studies in Dogs—In Vivo Dog PK

Prodrugs were administered to beagle dogs through intravenous (IV) andoral (P.O.) administrations in a non-crossover manner. The IV dose wasprepared in 20% hydroxypropyl β-cyclodextrin (HPBCD) and wasadministered via cephalic or saphenous vein. The P.O. dose was preparedin 10% polysorbate 80 (Tween 80) and was administered via gavage.

Blood samples were serially collected following dose administration forup to 48 hr and plasma was separated by centrifugation. Theconcentrations of prodrugs in dog plasma were determined by a LC-MS/MSassay following a protein precipitation step and addition of anappropriate internal standard (labetalol, imipramine or diclofenac).Quantification was done by determining peak area-ratios of the prodrugsand tenofovir to the internal standard. Additional blood sample(s) wascollected following dose administration for up to 24 hr. Peripheralblood mononuclear cells (PBMCs) were isolated by centrifugation, usingtubes and reagents specified for such application. The concentrations oftenofovir and/or its phosphate conjugate(s) in PBMCs were determined byan LC-MS/MS assay following a protein precipitation step and addition ofan appropriate internal standard (labetalol, imipramine or diclofenac).Quantification was done by determining peak area-ratios of tenofovirand/or its phosphate conjugate(s) to the internal standard.

Pharmacokinetic parameters were obtained using non-compartmental methods(Watson®). The area under the plasma concentration-time curve(AUC_(0-t)) was calculated from the first time point (0 min) up to thelast time point with measurable drug concentration using the lineartrapezoidal or linear/log-linear trapezoidal rule. The IV plasmaclearance was calculated by dividing the dose by AUC_(0-inf). Theterminal half-life of elimination was determined by unweighted linearregression analysis of the log-transformed data. The time points fordetermination of half-life were selected by visual inspection of thedata. The volume of distribution at steady state (Vd_(ss)) was obtainedfrom the product of plasma clearance and mean residence time (determinedby dividing the area under the first moment curve by the area under thecurve). The maximum plasma concentration (C_(max)) and the time at whichmaximum concentration occurred (T_(max)) were obtained by inspection ofthe plasma concentration-time data. Absolute oral bioavailability (% F)was determined from dose-adjusted IV and P.O. AUC ratios of the prodrug.Table 5 shows in vivo dog PK data in the form of TFV-DP concentrations(μM) in dog PBMCs at 24 h following a 10 mg/kg P.O. dose of theindicated prodrug.

TABLE 5 Viking, IC₅₀ Viking, IC₅₀ GI Tract In Vivo (10% NHS) (50% NHS)stability Dog PK Example (nM) (nM) (%) (μM)  1 >8403 >8403 2 >8403 >8403  3 7342 >8403  4 6464 >8403  5 >8403 >8403  6A 20.0 59.399.5 2.0  6B 257.9 494.3  7A 26.4 44.1 98.7  7B 378 393  8A 26.5 38.289.5  8B 439 531  9A 25.3 66.7 99.6  9B 378 800 10A 10.6 97.2 54.8 10B435 908 11A 21.5 103.5 11B 20.9 68.4 76.4 12A 41.7 119 12B 20.9 63.237.7 13A 8.7 56.4 38.7 13B 34.2 174.9 14A 16.6 70.2 38.3 14B 15.7 51.660.6 15A 19.6 146 15B 11.7 79.4 65.8 16A 6.1 18.6 12.7 1.3 16B 7.3 28.356.2 1.7 17A 6.5 43.0 30.5 17B 2.2 12.0 0 18A 65.0 134 99.2 18B 380971.20 19A 51.2 194.8 100 19B 3787 >8403 20A 858.6 4105 20B 112.5 431.899.3 21A 1458 8403 21B 269.8 836.1 22A 399.9 480.4 22B 83.8 290.8 99.223A >8403 >8403 23B 120.6 488.3 101 24A 0.8 4.4 76 37.5 24B 28.9 170 25A4.7 12.0 99.0 41.9 25B 590 >2000 100 26A 23.3 116.3 26B 1.5 6.8 96.923.8 28A 19.1 58.5 28B 2.1 5.7 83

1. A compound of structural Formula I:

or pharmaceutically acceptable salt thereof, wherein: R¹ and R² are eachindependently selected from (a) H, (b) —C₁₋₄alkyl, (c) —C₁₋₄alkylsubstituted with —OH, —SH, —SCH₃, —NH₂ or —NH—C(═NH)—NH₂, (d)—CH₂-phenyl, (e) —CH₂-phenol, (f) —(CH₂)₁₋₂—COOH, (g) —(CH₂)₁₋₂—CONH₂,(h) —CH₂-1H-indole, (i) —CH₂-imidazole, (j) aryl (for example but notlimited to phenyl or naphthyl) or (k) heteroaryl (for example but notlimited to pyridine); R³ is (a) —C₁₋₁₀alkyl unsubstituted or substitutedwith one to three substituents independently selected from fluoro,chloro, bromo, —OR^(10a), —SH, —NR¹¹R¹², —C₃₋₆cycloalkyl orspiro-C₃₋₆cycloalkyl, (b) —CH₂-phenyl unsubstituted or substituted withone to three substituents independently selected from fluoro, chloro,bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, (c) —C₃₋₈cycloalkylunsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15a), —SH,—NR¹¹R¹² or —C₁₋₃alkyl, (d) aryl unsubstituted or substituted with oneto three substituents independently selected from fluoro, chloro, bromo,—OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, (e) —C₁₋₅alkyl-X—C₁₋₅alkylwherein X is O, S or NH, (f) heteroaryl unsubstituted or substitutedwith one to three substituents independently selected from fluoro,chloro, bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, or (g) aheterocyclic ring unsubstituted or substituted with one to threesubstituents independently selected from fluoro, chloro, bromo,—OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl; R^(A) is an L-amino acid esterresidue of formula (i), a D-amino acid ester residue of formula (ii), aglycine ester residue of formula (iii), a geminally di-substituted aminoacid ester residue of formula (iv), a beta amino acid ester residue offormula (v), or an L-proline ester residue of formula (vi):

R⁴ is (a) —C₁₋₄alkyl, (b) —C₁₋₄alkyl substituted with —OH, —SH, —SCH₃,—NH₂, —NH—C(═NH)—NH₂, (c) —CH₂-phenyl, (d) —CH₂-phenol, (e)—(CH₂)₁₋₂—COOH, (f) —(CH₂)₁₋₂—CONH₂, (g) —CH₂-1H-indole, (h)—CH₂-imidazole, (i) aryl (for example but not limited to phenyl ornaphthyl) or (j) heteroaryl (for example but not limited to pyridine);R⁵ and R⁶ are each independently selected from (a) —C₁₋₄alkyl, (b)—C₁₋₄alkyl substituted with —OH, —SH, —SCH₃, —NH₂, —NH—C(═NH)—NH₂, (c)—CH₂-phenyl, (d) —CH₂-phenol, (e) —(CH₂)₁₋₂—COOH, (f) —(CH₂)₁₋₂—CONH₂,(g) —CH₂-1H-indole, (h) —CH₂-imidazole, (i) aryl (for example but notlimited to phenyl or naphthyl) or (j) heteroaryl (for example but notlimited to pyridine); or R⁵ and R⁶ are joined together with the carbonto which they are both attached to form —C₃₋₆cycloalkyl or a 4 to6-membered heterocyclic ring; R⁷ and R⁸ are each independently selectedfrom (a) H, (b) —C₁₋₄alkyl, (c) —C₁₋₄alkyl substituted with —OH, —SH,—SCH₃, —NH₂ or —NH—C(═NH)—NH₂, (d) —CH₂-phenyl, (e) —CH₂-phenol, (f)—(CH₂)₁₋₂—COOH, (g) —(CH₂)₁₋₂—CONH₂, (h) —CH₂-1H-indole, (i)—CH₂-imidazole, (j) aryl (for example but not limited to phenyl ornaphthyl) or (k) heteroaryl (for example but not limited to pyridine);R⁹ is (a) —C₁₋₁₀alkyl unsubstituted or substituted with one to threesubstituents independently selected from fluoro, chloro, bromo,—OR^(10b), —SH, —NR¹³R¹⁴, —C₃₋₆cycloalkyl or spiro-C₃₋₆cycloalkyl, (b)—CH₂-phenyl unsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15b), —SH,—NR¹³R¹⁴ or —C₁₋₃alkyl, (c) —C₃₋₈cycloalkyl unsubstituted or substitutedwith one to three substituents independently selected from fluoro,chloro, bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, (d) arylunsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15b), —SH,—NR¹³R¹⁴ or —C₁₋₃alkyl, (e) —C₁₋₅alkyl-X—C₁₋₅alkyl wherein X is O, S orNH; (f) heteroaryl unsubstituted or substituted with one to threesubstituents independently selected from fluoro, chloro, bromo,—OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, or (g) a heterocyclic ringunsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15b), —SH,—NR¹³R¹⁴ or —C₁₋₃alkyl; R^(10a) and R^(10b) are each independentlyselected from —H or —C₃₋₆cycloalkyl; R¹¹ and R¹² are each independentlyselected from —H, —C₁₋₃alkyl or —C₃₋₆cycloalkyl; R¹³ and R¹⁴ are eachindependently selected from —H, —C₁₋₃alkyl or —C₃₋₆cycloalkyl; andR^(15a) and R^(15b) are each independently selected from —H, —C₁₋₃alkylor —C₃₋₆cycloalkyl.
 2. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein one of R¹ and R² is H, and the other isH or —C₁₋₄alkyl.
 3. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof wherein R³ is (a) —C₁₋₈alkyl, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, (b)—CH₂-phenyl, unsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15a), —SH,—NR¹¹R¹² or —C₁₋₃alkyl, (c) —C₃₋₆cycloalkyl, unsubstituted orsubstituted with one to three substituents independently selected fromfluoro, chloro, bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, (d)phenyl or naphthyl, each unsubstituted or substituted with one to threesubstituents independently selected from fluoro, chloro, bromo,—OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl, (e) —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃, —CH₂CH₂NHCH₃, —CH₂CH₂CH₂NHCH₃, (f) pyridyl,unsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15a), —SH,—NR¹¹R¹² or —C₁₋₃alkyl, or (g) piperidinyl, pyrrolidinyl,tetrahydrofuranyl, or tetrahydropyranyl, each unsubstituted orsubstituted with one to three substituents independently selected fromfluoro, chloro, bromo, —OR^(15a), —SH, —NR¹¹R¹² or —C₁₋₃alkyl.
 4. Thecompound of claim 3 or a pharmaceutically acceptable salt thereofwherein R³ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.
 5. The compound of claim 4 or a pharmaceutically acceptablesalt thereof wherein R³ is —C₃₋₈alkyl.
 6. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein R⁹ is (a) —C₁₋₈alkyl,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂SH, —CH₂CH₂CH₂SH, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, (b) —CH₂-phenyl, unsubstituted or substituted with one tothree substituents independently selected from fluoro, chloro, bromo,—OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, (c) —C₃₋₆cycloalkyl,unsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15b), —SH,—NR¹³R¹⁴ or —C₁₋₃alkyl, (d) phenyl or naphthyl, each unsubstituted orsubstituted with one to three substituents independently selected fromfluoro, chloro, bromo, —OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, (e)—CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂SCH₃, —CH₂CH₂CH₂SCH₃, —CH₂CH₂NHCH₃,—CH₂CH₂CH₂NHCH₃, (f) pyridyl, unsubstituted or substituted with one tothree substituents independently selected from fluoro, chloro, bromo,—OR^(15b), —SH, —NR¹³R¹⁴ or —C₁₋₃alkyl, or (g) piperidinyl,pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, eachunsubstituted or substituted with one to three substituentsindependently selected from fluoro, chloro, bromo, —OR^(15b), —SH,—NR¹³R¹⁴ or —C₁₋₃alkyl.
 7. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R^(A) is:

and R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.
 8. The compound of claim 2 or a pharmaceutically acceptablesalt thereof, wherein R^(A) is:

R⁴ is —C₁₋₄alkyl and R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl.
 9. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein R^(A) is:

R⁵ and R⁶ are each independently selected from —CH₃, —CH₂CH₃, —C₃alkylor —C₄alkyl, and R⁹ is —C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl.
 10. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof, wherein R^(A) is:

R⁷ is H or —C₁₋₄alkyl, R⁸ is H or —C₁₋₄alkyl, and R⁹ is —C₁₋₈alkyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
 11. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof wherein: R¹ is Hor —C₁₋₄alkyl; R² is H or —C₁₋₄alkyl; R³ is —C₁₋₈alkyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; R⁴ is —CH₃; R⁵ and R⁶ are both—CH₃; R⁷ is H or —C₁₋₄alkyl; R⁸ is H or —C₁₋₄alkyl; and R⁹ is—C₁₋₈alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
 12. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein: one of R¹ and R² is H, and the other is methyl or i-propyl; R³is i-propyl; R⁴ is —CH₃; R⁵ and R⁶ are both —CH₃; R⁷ is H or —C₁₋₄alkyl;R⁸ is H or —C₁₋₄alkyl; and R⁹ is —C₃₋₈alkyl, cyclobutyl, cyclopentyl orcyclohexyl.
 13. (canceled)
 14. A pharmaceutical composition comprisingan effective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 15.The pharmaceutical composition of claim 14 further comprising aneffective amount of one or more additional HIV antiviral agent selectedfrom HIV protease inhibitors, HIV integrase inhibitors, non-nucleosideHIV reverse transcriptase inhibitors, nucleoside HIV reversetranscriptase inhibitors, HIV fusion inhibitors and HIV entryinhibitors.
 16. A method for the prophylaxis or treatment of infectionby HIV or for the prophylaxis, treatment, or delay in the onset of AIDSin a subject in need thereof which comprises administering to thesubject an effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.
 17. The method of claim 16wherein the subject is human.
 18. The method of claim 17 furthercomprising administering to the human an effective amount of one or moreadditional HIV antiviral agent selected from HIV protease inhibitors,HIV integrase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusioninhibitors and HIV entry inhibitors. 19-21. (canceled)
 22. Thepharmaceutical composition of claim 14 further comprising an effectiveamount of one or more additional HIV antiviral agent selected from:abacavir, abacavir sulfate, abacavir+lamivudine,abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavirsulfate, AZT, capravirine, darunavir, ddC, ddI, delavirdine, delavirdinemesylate, dolutegravir, doravirine, efavirenz,efavirenz+emtricitabine+tenofovir DF,4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine,emtricitabine+tenofovir DF, emvirine, enfuvirtide, enteric coateddidanosine, etravirine, fosamprenavir calcium, indinavir, indinavirsulfate, lamivudine, lamivudine+zidovudine, lopinavir,lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate,nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir,saquinavir mesylate, stavudine, tipranavir and vicriviroc.